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Asymmetric Epoxidation of Chalcones with Chirally Modified Lithium and Magnesium tert-Butyl Peroxides.

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considerably photosensitive, their analytical characterization
was performed analogously to that of the isocyanato complexes.
Finally, we were able to show that without nitrene scavengers
CT excitation of 1-4 yields coordinatively unsaturated metal
complex fragments of the kind [Nio("P2")](lb-4b). These species initiate, for instance, the photoinduced catalytic cyclotrimerization of methyl propiolate (9) to trimethyl benzene1.3.5.-tricarboxylate (10). Thus, irradiation of 2 in CH2CI,
leads exclusively to the formation of 10 as shown by GCMS[16](see Scheme 1).
Thus the photolysis of 1-4 depends strongly on the substrates
used and differs completely from that of the analogous complexes of the heavier ds-metal ions Pd" and Pt".['. 3c1 Moreover, the
single steps according to Scheme 1 open a convenient photochemical entry to reactive intermediates. Their use in photocatalytic systems is the subject of further investigations.
Received July 21, 1996 [293681E]
German version: Angew Chem. 1997, 109. 373-375
Keywords: insertions
N ligands
. nickel
- nitrene
[I] H Hennig, R. Stich, H. Knoll, D. J Stufkens, Cuord Chem. Rev. 1991, 111.
[21 T. Jin, T. Suzuki, T. Imamura, M. Fujimoto, Inorg. Chem. 1987, 26, 1280.
[ 3 ] a) C. Bartocci, F. Scandola, J Chem. Soc. D 1970,230; b) A. Vogler, C. Quett,
H. Kunkeiy, Ber. Bunsengcs Phjs. Chem. 1988,92,1486; c ) H. Knoll, R. Stich,
H. Hennig, D. 3. Stufkens, Inorg. Chim. Acra 1990. 178, 71.
141 F. Basolo. J Indion Chem. Sor. 1977, 54, 7.
[S] H. D. Gafney, J. L. Reed, F. Basolo, J. Am. Chem. So?. 1973, 95, 7998.
[6] J. L. Reed, H. D. Gafney, F. Basolo, J. Am. Chem. Suc. 1974, Y6, 1363.
171 R. Ngai, Y.-H. L. Wang, J. L. Reed, Inorg. Chem. 1985. 24, 3802.
[S] M. E. Sigman, T. Aubrey, G B. Schuster, J Am. Chem. Sot.. 1988, 110,
191 a) K. von Werner, W Beck, Chem Ber. 1972, 105, 3209; b) W. Beck,
J. Organomer. Chew. 1990, 383, 143.
[lo] The synthesis of 1-4 was adapted from K. Bowman, 2. Dori, Inorg. Chem.
1970, 9, 395.
[ I l l J Chatt, F. A. Hart, J. Chem. Soc. 1960. 1378.
[12] For instance, polychromatic irradiation (8 h, i"'<320 nm) of 2 (270 mg) In
CH,CI, (50 mL) under argon in a Schlenk tube fitted with a glass filter, separation from [Ni(N,),] and disposal by dilute HCI, precipitation of 2b with
mhexane. separation from remaining 2 by recrystallization from xylene until
IR spectroscopy no longer showed N; bands; orange-yellow needles, yield
160 mg of 2b ( z75 %).
[13] Hydrogen balance is achieved by traces of water in the solvents used and during
the treatment of the photolysis products with water.
[I41 G. Swift. D. Swern, Org. Chem. 1967, 13, 511.
[I51 a) P. L. Goggin, R. J. Goodfellow, J. Clren?.Sot.. A 1966, 1462: b) R C. R.
Coussmaker. M. H. Hutchinson, J. R. Mellor, L. E. Sutton, L. M . Venanzi,
{bid. 1961. 2705.
[I61 For instance, polychromatic irradiation (;."I>
320 nrn) of 50 rng 2 in 20 mL
CH,Cl, under argon in a Schlenk tube fitted with a glass filter. in the presence
ofg(1.1 &yields IO(0.7Og. -64%);estirnationoftheproduct yield by means
of GC (calibration by commercially available 9).
Asymmetric Epoxidation of Chalcones with
Chirally Modified Lithium and Magnesium
tert-Butyl Peroxides**
Catherine L. Elston, Richard F. W. Jackson,*
Simon J. F. MacDonald, and P. John M u r r a y
The asymmetric epoxidation of alkenes is central to many of
the recent developments in the stereoselective synthesis of chiral
molecules. The discovery of catalytic methods for the asymmetric epoxidation of allylic alcohols,[']and of alkenes with isolated
double bonds,[*]has been the starting point for the preparation
of a wide variety of valuable, enantiomerically enriched intermediates. The asymmetric epoxidation of electron-deficient alkenes, specifically chalcone derivatives, has also been studied.
The most efficient process known to date employs basic hydrogen peroxide in a three-phase system in which polypeptides are
used as the source of chirality.[31Very recently, efforts to extend
this method to other substrates have met with some S U C C ~ S S . ~ ~ ]
Other methods for the asymmetric epoxidation of unsaturated
ketones exist,[51although they appear not to have the utility of
the polypeptide-based system. Enders et a1.[61recently reported
the efficient stoichiometric asymmetric epoxidation of electrondeficient alkenes by using chirally modified zinc alkyl peroxides.
This is the first report on the use of chirally modified metal alkyl
peroxides, in which the alkyl peroxide fragment is a nucleophilic
oxidant rather than an electrophilic oxidant (as is the case for
the Sharpless epoxidation).['' Herein we report our own results
on the asymmetric epoxidation of chalcone derivatives by using
other, chirally modified metal alkyl peroxides.
Given the stereospecific nature of the epoxidation of electrondeficient alkenes with lithium tert-butyl hydroperoxide,"]
(which is easily prepared by the addition of n-butyllithium in
hexanes to a solution of tert-butyl hydroperoxide in toluene) we
first sought to develop a stoichiometric asymmetric epoxidizing
agent by the addition of chiral modifiers. We chose chalcone 1 a
as the substrate in view of the precedent regarding its U S ~ . [ ~ - ~ ]
The epoxidation of l a with lithium tert-butyl peroxide in
toluene, in the absence of chiral modifiers, proceeds rapidly and
in high yield (90%, 1 h). After screening a variety of ligands
(tartrate diesters, S,S-1
,2-diphenylethane-l,2-diol, ( -)ephedrine, ( - )-N-methylephedrine, and simple chiral alcohols),
it became clear that good yields of the enantiomerically enriched
epoxide (+)-2a could be obtained. The best results were
achieved by using (+)-diethy1 tartrate (1.1 equiv) as the chiral
modifier in toluene (Scheme 1); this reaction provided the chalcone epoxide (+)-2a after two days (71-75OA yield, 62% ee).
Reactions carried out in the presence of a chiral ligand, specifically (+)-diethy1 tartrate, did not proceed at all in the absence
of an additional equivalent of lithium butoxide (or other lithium
41 0
VCH Verlagsgesellschufr mhH, 0-69451 Weinherm. 1997
Prof. Dr. R. F. W. Jackson, Dr. C. L. Elstoii
Department of Chemistry
Bedson Building, University of Newcastle
Newcastle upon Tyne, N E l 7RU (UK)
Fax: Int. code +(191)222-6929
Dr. S. J. F. MacDonald
Glaxo Wellcome Research and Development, Stevenage (UK)
Dr. P. J. Murray
Glaxo Wellcome Cambridge Chemistry Laboratory (UK)
This work was supported by Glaxo Wellcome under the EPSRCiDTI LINK
Asymmetric Synthesis Programme. We thank C. S . Dexter for additional experimental work, F M C Corporation (UK) Limited for a generous gift of nbutyllithium and Professor Dr. D. Enders, Aachen, for sharing his results prior
to publication. R.F.W.J. thanks the Nuffield Foundation for a One Year Science
Research Fellowship.
0570-0~33!97/3604-0410.$15.00+ 25j0
Angull. Chem. Int. Ed. Engl. 1997. 36, No. 4
tBuOOH (1.5 equiv)
Bu2Mg (0.1 equiv)
62% ee
Scheme 2. Catalytic asymmetric epoxidation of chalcone derivatives with magnesium ter/-butyl peroxide in the presence of (+)-DET.
Scheme 1. Stoichiometric asymmetric epoxidation of chalcone with lithium tertbutyl peroxide in the presence of (+)-diethy1 tartrate ((+)-DET).
alkoxide) . The latter reagent could easily be included by addition of butanol (1 equiv) to the solution of tert-butyl hydroperoxide (1.5 equiv) in toluene prior to the addition of n-butyllithium (2.1 equiv) . Addition of coordinating solvents such as
THF suppressed the reaction substantially. Despite much effort,
no better ligand was discovered, and attempts to perform the
epoxidation with less than stoichiometric amounts of the
reagent met with no success.
In order to develop a catalytic system, commercially available
dibutylmagnesium was employed in place of n-butyllithium. In
a preliminary experiment, it was established that epoxidation of
chalcone with tert-butyl hydroperoxide and catalytic amounts
of dibutylmagnesium (0.2 equiv, solution in heptane) in toluene
gave racemic chalcone epoxide 2a in high yield (90 YO).Addition
of dibutylmagnesium (1 equiv) to a solution of tert-butyl hydroperoxide (1.5 equiv, 3.7111 in toluene) in additional toluene
(10 mL on a 2 mmol scale) resulted in the formation of a gel,
which dissolved upon addition of ( +)-diethy1 tartrate (1 equiv) .
Addition of chalcone to this solution led to a slow epoxidation,
which after two days afforded (-)-chalcone epoxide 2a in satisfactory yield (51 %) and with improved enantiomeric purity
(78 % re). Surprisingly, the product had the opposite absolute
configuration to that obtained by using the lithium alkyl peroxide, even though the same chiral ligand had been employed. This
observation indicates that there are substantial differences between the two reactions.
Reduction in the amount of dibutylmagnesium (relative to
the amount of (+)-diethy1 tartrate) employed resulted in an
increase in the enantiomeric excess of the product (to 93 Yo ee in
the case of 0.2 equiv of Bu,Mg), although there was a substantial decrease in the reaction rate and yield. Since the use of a
catalytic system implies that the concentration of the catalytic
intermediate is lower than in a stoichiometric reaction, we simply omitted the additional toluene, and added the chalcone 1 a
as a solid. The only solvent, therefore, was that derived from the
reagents dibutylmagnesium and tert-butyl hydroperoxide. Under these concentrated conditions, the amount of both dibutylmagnesium and (+)-diethy1 tartrate may be reduced (to as little
as 5 mol % and 6 mol%, respectively). Satisfactory yields (40 to
60 YO)and good levels of enantiomeric excess ( > 90 % re) are
obtained, provided that there is a small excess of (+)-diethy1
tartrate over dibutylmagnesium. The best compromise between
the amount of catalyst required and yield of product was
achieved by using 10 mol % dibutylmagnesium and 11 mol YO
(+)-diethy1 tartrate.
Having developed a new catalytic asymmetric epoxidation of
chalcone, we then sought to explore the generality of the process
by using related unsaturated ketones 1. A practical difficulty is
that many substrates are essentially insoluble in the small
amounts of toluene and heptane in which the epoxidation is
conducted. Although the detrimental effect of polar solvents
(specifically THF) in the asymmetric lithium lert-butyl peroxide
epoxidations had already been established, addition of small
amounts of THF allowed the substrates to dissolve, and did not
compromise the enantiomeric excess (Scheme 2, Table 1).
Angeti Chem In1 Ed Engl 1997, 36, Rio 4
Table 1. Asymmetric epoxidation of chalcone derivatives 1 with tert-butyl hydroperoxide by using dibutylmagnesium (10 mol%) and diethyl tartrate (11 mol%)
on a 10 mmol scale.
THF[mL] Product
Yield [%I ee[al [n],[b]
[a] All CP values were determined by chiral phase HPLC (Daicel Chiralcel O D
column) by using 95: 5 heptanelethanol (flow rate 1.0 mLmin-I). [b] Specific rotations were recorded in CH,CI, ( c = I ) . [c] (-)-Diethy1 tartrate was used in place of
(+)-diethy1 tartrate.
The results obtained for the chalcone substrates are comparable with, or better than, those achieved by using the optimized
polypeptide-based systems. At present, our working hypothesis
is that the active catalyst is a magnesium bis(a1koxide) derived
from (+)-diethy1 tartrate. It appears that the chiral ligand binds
the magnesium cation so tightly that effective catalytic asymmetric induction is possible despite the substantially reduced
reactivity of the magnesium peroxide when the ligand is bound.
Since all the components used in this process are commercially available at relatively low cost, we believe that it may be of
preparative value. Further development is underway, which
may provide a general procedure for the catalytic asymmetric
epoxidation of electron-deficient alkenes.
Experimental Section
An anhydrous solution of terr-butyl hydroperoxide ( 3 . 7 ~in toluene [9], 4.05 mL,
15 mmol) was placed under a nitrogen atmosphere in a dry 50 mL flask w3ith side
arm (septum) and dibutylmagnesium ( I M in heptane, 1.0 mL, 1 mmol) [lo] was
added dropwise by syringe at room temperature. After the evolution of butane, a
colorless gel was formed, which was stirred at room temperature for 1 h. (+)-Diethyl tartrate (0.19 mL, 1.1 mmol) w a s added in one portion and the mixture wab
stirred at room temperature for 1 h, resulting in a colorless solution. Chalcone l a
(2.08 g, 10 mmol) was added as a solid in one portion (together with f'reshly distilled
T H F in the case of the less soluble substrates, as indicated in Table 1). After 24 h at
room temperature (TLC sampling) the reaction was quenched with saturated
aqueous NH,C1 (lOmL), and 10% aqueous Na,SO, (15mL) and Et,O (10mL)
were added. The aqueous layer was washed with Et,O (3 x 10 mL), the combined
organic extracts were washed with saturated aqueous NaCI, dried over MgSO,, and
the solvent was removed under reduced pressure. After purification by flash chromatography on silica gel (petroleum ether (40/60):EtOAc 20: 1) the n,b-epoxyketone
(-)-2a was obtained. (+)-Diethy1 tartrate can be recovered quantitatively with no
observable change in enantiomeric purity from the same chromatographic column
by increasing the proportion of EtOAc in the eluent.
Received: August 6, 1996 [Z94271E]
German version: Angeii. Chem 1997, 109, 379-381
Keywords: asymmetric catalysis
lithium magnesium
[ l ] R. A. Johnson, K. B. Sharpless in Catalytic A.symmc~tric Syntheslr (Ed.:
I. Ojima), VCH, New York, 1993, 103.
[2] a) E. N . Jacobsen in C a ~ u l j t i cAsymmetric Synthesis (Ed.: I. Ojima), VCH,
New York, 1993, 159; b) T. Katsuki. Coorti. Clwnz. Rev. 1995, 140, 189-214.
For a recent paper, see: A. Kumar. V Bhakuni. Tetrahedron Lett. 1996. 37,
Verlagsgesellschaft mhH D-69451 Weinhelm 1997
0570-0833 97 3604-0411 $ 1 5 OO+ 25 0
41 1
a) S. Julia, J. Masana, J. C. Vega, AngeM’. Chem. 1980, 92,968; Angew. Chem.
Int. Ed. Engl. 1980, 19, 929; b) S. Itsuno, M. Sakakura, K. Ito, J. Org. Chem.
1990, 55, 6047; c) P. W. Baures. D. S. Eggleston, J. R. Flisak, K. Gombatz, I.
Lantos. 5%’. Mendelson. J. R. Remich, Tetrahedron Lett. 1990, 31, 6501, and
references therein.
a) M. E. Lasterra-Sanchez, S. M. Roberts, J. Chem. SOC.Perkin Truns. f 1995,
1467; b) M. E. Lasterra-Sanchez, U. Felfer, P. Mayou, S. M. Roberts, S. R.
Thornton, C. J. Todd, ibid. 1996,343; cj W Kroutil, P. Mayon. M. E. LasterraSanchez, S. J. Maddrell, S. M. Roberts, S. R. Thornton, C. J. Todd. M. Tiiter.
Chem. Conzmun. 1996, 845.
a) R. Helder, J. C. Hummelen, R. W. P. M. Laane, J. S . Wlering, H. Wynberg,
Tetrahedron Lelt. 1976, 1831; h) S. Colonna, A. Manfredi, R. Annunziata, N.
Gaggero, L. Casella, J. Org. Chem. 1990,55,5862; cj S. Colonna, N. Gaggero.
A. Manfred], A. M. Spadoni, L. Casella, G. Carrea, P. Pasta, Tetrahedron
1988,44, 5169; dj C. Baccin, A. Gusso. F. Pinna, G. Strukul, Organometal1ic.r
1995, 14, 1161.
D. Enders, J. Zhu, G. Raahe, Angew. Chrm. 1996, f08,1827; Angew. Chem. I n f .
Ed. Engl. 1996, 35, 1125.
[7] For structural studies on metal alkyl peroxides, see: a) G. Boche, K. Mobus,
K. Harms, J. C. W. Lohrenz, M. Marsch, Chem. E w . J. 1996, 2, 604; h) G.
Boche, K. Mobus, K. Harms, M. Marsch, J. Am. Chem. Soc., 1996,1f8,2770,
and references therein.
[XI 0. Meth-Cohn, C. Moore, H. C. Taljaard, J. Chem. SOC.Perkin Trans. 1 1988,
Org. Chem. 1983, 4K, 3607.
[9] I . G. Hill. B. E. Rossiter, K. B. Sharpless, .
[lo] Dihutylmagnesium in heptane was purchased from Aldrich.
The title of the communication by A. Krebs, K.-I. Pforr,
W. Raffay, B. Tholke, W. A. Konig, I. Hardt, and R. Boese
(Angew. Chem. Int. Ed. Engl. 1997,36, 359-160) should read
“A Stable Hetero-trans-cycloheptene” and not “A Stable
Hetero-trans-cyclopentene” .
S E P T E M B17
- 2 0 , 1997
The Second International Conference on the Chemistry of the Alkali and Alkaline Earth Metals succeeds the
First Conference held in Cambridge, England, in 1994. The Conference will be organized by Paul von Rague
Schleyer and Walter Bauer (both Erlangen). Two events will contribute to the scope of the Conference: the 100th
birthday of Georg Wittig and the impending retirement of Paul Schleyer from Erlangen.
The Conference will consist of 26-28 plenary and invited lectures. Lecturers who have agreed so far:
I? Bickelhaupt, G Boche, IZ Bock, L. Brandsma, FK Clegg, D. Collum, 0.Davidsson, U.Edlund, IZ Giinther,
R FK Hoflmann, N. J. R. van Eikema Hommes, D. Hoppe, G Klumpp, A. Maercker, C. Marsden, H. Reich,
D. Seebach, R. Snaitli, D. Stalke, A. Streitwieser, R mlliard, D. Wright
For further information please contact: Priv.-Doz. Dr. Walter Bauer, Institute of Organic Chemistry, University
of Erlangen-Nuremberg, Henkestrasse 42, D-9 1054 Erlangen, Germany, Phone +49-9 131-852987, FAX
+49-913 1-859132, e-mail
The proceedings of the Conference and pre-registration facilities are available on WWW: (Germany mirror site) (US mirror site)
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asymmetric, peroxide, butyl, chalcones, modified, magnesium, epoxidation, chirally, tert, lithium
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