Chiral aluminum complexes as catalysts in asymmetric Baeyer-Villiger reactions of cyclobutanones

Article abstract of DOI:10.1139/v01-137

BINOL-aluminum complexes were successfully employed as mediators and catalysts in asymmetric Baeyer-Villiger rearrangements of cyclobutanones. Good enantioselectivies were achieved with only 15 mol% of the chosen chiral Lewis acid. The enantiomeric excesses obtained have never been reached before in such metal-catalyzed Baeyer-Villiger reactions.

Full text of DOI:10.1139/v01-137

1593
Chiral aluminum complexes as catalysts in
asymmetric Baeyer-Villiger reactions of
cyclobutanones
Carsten Bolm, Oliver Beckmann, and Chiara Palazzi
Abstract: BINOL-aluminum complexes were successfully employed as mediators and catalysts in asymmetric Baeyer-
Villiger rearrangements of cyclobutanones. Good enantioselectivies were achieved with only 15 mol% of the chosen
chiral Lewis acid. The enantiomeric excesses obtained have never been reached before in such metal-catalyzed Baeyer-
Villiger reactions.
Key words: aluminum, asymmetric catalysis, lactones, oxidations, rearrangement.
Resumé : Des complexes d’aluminium-BINOL ont été employés avec succès en tant que médiateurs et catalyseurs dans
des réactions de Baeyer-Villiger asymétriques de cyclobutanones. Avec des taux catalytiques pouvant aller jusqu’à seu-
lement 15 mol% en acide de Lewis chiral, il a été possible d’obtenir des excès énantiomériques jamais atteints aupara-
vant dans de tels oxydations de Baeyer-Villiger catalysées par des métaux.
Mots clés : aluminium, catalyse asymétrique, lactones, oxydation, réarrangement.
Introduction
To the best of our knowl1e5d9g7e thBisoilms thete afil.rst example of a
main group metal complex that can mediate in substoichiometric
amounts asymmetric Baeyer-Villiger oxidations.4 The ꢀ-
butyrolactones formed are valuable intermediates in the syn-
thesis of pharmaceuticals or natural products, particularly
when they are obtained in an enantiomerically pure form,
and hence there is a notable effort to gain synthetic access to
these important building blocks (7).
More than 100 years after its discovery, the Baeyer-Villiger
oxidation has become a valuable tool in organic synthesis,
owing to its tolerance of functional groups, its regio-
selectivity, and retention of configuration during the migra-
tion step (1). However, the search for an asymmetric metal
catalysis for this rearrangement is still a challenging task in
modern chemistry. The metal systems that have been devised
to render the reaction asymmetric either lack a broader scope
of substrates and enantioselectivity or exhibit the drawback
of relying on stoichiometric amounts of the metal (2).3 Ex-
isting catalytic procedures employ platinum (3) or copper
complexes (4), while (over)stoichiometric variants make use
of titanium, tin, zinc, or zirconium (5). These approaches
have in part provided appreciable results with respect to
enantiomeric excesses, but none represent a practical, synthet-
ically useful method. Thus, further development in this field
of asymmetric oxygen insertion is still necessary.
In the present report we introduce a novel catalyst involv-
ing a BINOL-aluminum promoter, which has already been
successfully applied to other reactions (6): the combination
of Me2AlCl with enantiopure BINOL under a dry, inert gas
atmosphere furnishes a catalyst, which is able to oxidize
cyclobutanones in an enantioselective manner upon addition
of a hydroperoxide (Scheme 1).
Results and discussion
In principle, if a bicyclic cyclobutanone derivative such as
1 is oxidized, two regioisomeric lactones may be formed,
since the insertion of oxygen can occur on either side of the
carbonyl group. Thus, when the racemic bicyclooctanone 1
was used as the substrate, the novel Al-mediated oxidation
afforded not only 7-oxabicyclo[4.3.0]nonan-8-one (2a),
which is the normal predominately formed lactone in com-
mon Baeyer-Villiger reactions (1), but also its regioisomer,
8-oxabicyclo[4.3.0]nonan-7-one (2b), in fairly large quantity.
With (S)-BINOL in combination with Me2AlCl (metal-to-
ligand ratio = 1:1, 50 mol%), the products were (+)-(1R,6R)-
2a with 34% ee and (+)-(1R,6S)-2b with 96% ee, exhibiting
a remarkably low ratio 2a:2b of 2.7 (Table 1, entry 1). Ap-
parently, this transformation represents an example of an
enantiodivergent reaction. Hence, the regioisomeric, enantio-
Received February 7, 2001. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on October 26, 2001.
This article is dedicated to Professor Victor Snieckus for his outstanding contributions to the art of organic synthesis.
C. Bolm,1 O. Beckmann,2 and C. Palazzi. Institut für Organische Chemie der RWTH Aachen, Prof.-Pirlet-Str. 1, D-52056
Aachen, Germany.
1Corresponding author (telephone: +49 241 80 946 75; fax: +49 241 80 92 391; e-mail: carsten.bolm@oc.rwth-aachen.de).
2Present address: UMR 6509 CNRS, Université de Rennes 1, Organométalliques et Catalyse, Campus de Beaulieu, F-35042 Rennes
CEDEX, France.
3For reviews on asymmetric metal-mediated Baeyer-Villiger reactions see ref. 2.
4The aforementioned nonstoichiometric variants known to date are based on transition metals platinum or copper (3, 4).
Can. J. Chem. 79: 1593–1597 (2001)
DOI: 10.1139/cjc-79-11-1593
© 2001 NRC Canada

1594
Can. J. Chem. Vol. 79, 2001
Scheme 1.
During the evaluation of the new Al-based Baeyer-Villiger
system, different metal sources were employed. Aluminum
reagents such as EtAlCl2, AlCl3, and Al(O-t-Bu)3 in combi-
nation with BINOL did not lead to complete oxidation and
afforded products with low ee’s. Me3Al with BINOL al-
lowed full conversion but gave a racemate. Solely when
dialkyl aluminum chlorides (R2AlCl with R = Me, Et) were
used was the reaction successful. Of the compounds tested,
the dimethyl derivative gave somewhat higher enantiomeric
excesses than the diethyl metalhalide (e.g., 71 vs. 63% ee for
lactone 8 and 68 vs. 54% ee for lactone 10). The different
performances of dialkyl precursors with BINOL as ligand
may be indicative of an intricate, oligomeric active species.
Since Me3Al is not an appropriate metal source, even though
O
Me2AlCl + (S)-BINOL (1 : 1)
1.5 eq. PhC(CH3)2OOH
toluene, –25°C -> r.t.
rac-1
O
6
1
6
O
+
O
O
1
(+)-(1R,6S)-2b
(+)-(1R,6R)-2a
it readily reacts with diols,
a simple mononuclear
merically enriched lactone 2a is produced chiefly from one
enantiomer of the racemic starting material rac-1, while the
substrate antipode gives rise to the other nonracemic regioiso-
meric product 2b. Such a behavior has previously been found
in biocatalytic Baeyer-Villiger reactions (8) and in the copper-
catalyzed Baeyer-Villiger oxidation of the same substrate,
rac-1 (4b). Mathematically it was described by Kagan (9).
Furthermore, the bicyclic, commercially available ketone
rac-3 and the indene-derived cyclobutanone rac-5 each led
to two regioisomeric lactones (Table 1, entries 2 and 3).
Here, the ratio a:b of regioisomers had shifted even more in
favor of the unusual Baeyer-Villiger product (i.e., toward 4b
and 6b, respectively). In parallel, the enantiomeric excesses
of either lactone are leveling to nearly the same value. In ad-
dition, under the applied conditions, the olefinic ketone rac-
3 did not seem susceptible to epoxidation according to GC
analysis.
(BINOL)AlMe structure formed by reaction of BINOL with
Me2AlCl may be excluded as the catalyzing complex, since
it should also be expected to be formed from Me3Al. On the
other hand a (BINOL)AlCl species cannot play a decisive
role in the enantioselection because of the aforementioned
influence of the alkyl rest, i.e., alkyl groups are likely to be
still bound to an active aluminum complex. Thus, aluminum
catalyst(s) incorporating two or more metal centers and
bridging ligands are probable.6
A survey of various chiral diols as ligands revealed the
binaphthyl scaffold to be the most effective one for achieving
OH
OH
OH
HO
Besides the racemic disubstituted ketones 1, 3, and 5,
prochiral 3-monosubstituted cyclobutanones 7, 9, 11, 13, and
15 were also tested. These are accessible by means of [2+2]-
cycloaddition of dichloroketene to an olefin with subsequent
dehalogenation (11). The oxidation of 3-phenylcyclobutanone
(7) yielded the corresponding lactone with 71% ee when
50 mol% of the Al-BINOL mixture was used (Table 1, entry
4). On reducing the catalyst loading to 15 mol%, the ee
dropped only slightly to 68%,5 which is the highest value
reached to date in metal-catalyzed Baeyer-Villiger reactions
of this substrate (2, 4d).
(S,S)-17
(S)-18
CH3
Br
OH
OH
OH
OH
Neither the introduction of a chloro substituent on the arene
nor the replacement of the aromatic substituent by an alkyl
group at positon C3 had a detrimental effect with respect to
the conversion and enantiomeric excess (Table 1, entries 5
and 6). In addition, 3-benzylcyclobutanones, whose lactones
are intermediates in syntheses of pharmaceuticals and
lignanes (7e, 12), proved to be suitable substrates for this (cat-
alytic) asymmetric transformation. Albeit, piperonyl lactone
16 showed a modest ee of 58% in comparison to lactone 14
with 73% ee (Table 1, entries 7 and 8). All oxidations were
complete within 12 h. No ketone could be detected by GC
analysis and lactones 10 and 14 were isolated after column
chromatography in 82 and 87% yield, respectively.
CH3
Br
(S)-19
(R)-20
Br
OH
OH
(S)-21
Br
5 A reduction of catalyst loading to 15 mol% was possible with 4-chlorophenyl cyclobutanone 9 as well (ee dropped from 68 to 57% at full
conversion), but not with bicyclooctanone rac-1. In the latter case full conversion with 25 mol% of BINOL-Al (1:1) could no longer be
achieved. However, when 25 mol% of BINOL and 50 mol% of Me2AlCl were used, the oxidation of rac-1 was still complete, albeit the
enantioselectivity deteriorated (2a: 5% ee; 2b: 80% ee).
6 A similar interpretation was supported by 27Al NMR studies and molecular weight determinations as described in ref. 13.
© 2001 NRC Canada

Bolm et al.
1595
Table 1. Asymmetric Baeyer-Villiger reaction of various cyclobutanone derivatives medi-
ated by the (S)-BINOL-Al system (50 mol%).
Note: For details see Experimental. (R)-BINOL as ligand gave the same results yet with inverted
absolute configuration of the product.
aCalculated from area percentages in the GC.
bThe ee analysis by chiral GC did not give baseline-separated signals.
enantioselectivity. Me2AlCl in combination with L-diethyl
tartrate, (R,R)-TADDOL, dianhydro D-mannitol, or D-erythrono
lactone was not able to promote an asymmetric oxidation of
ketone rac-1 and 7, and in some cases even failed to afford
full conversion to the corresponding lactones. Furthermore,
nitrogen-containing diols (salen-type ligands) prevented the
ketones from being oxidized, which is consistent with the
observed inhibitory effect of additives such as triethylamine,
triphenylphosphine oxide, or tetrahydrofuran bearing coordi-
nating sites. Eventually, it was (S,S)-hydrobenzoin 17, (S)-
BIPHENH2 18 (14a), and BINOL and derivatives thereof, in
particular 21 (14b), that brought about noticeable enantio-
meric excesses with a full conversion.
The test reaction involving 3-phenyl cyclobutanone (7) as
the substrate and 3,3>-disubstituted BINOLs such as 19, with
two bromo substitutents, or BINOL with two biphenyl or
naphthyl moieties, at C3 and C3> (15), respectively, merely
led to racemic lactones if they showed full conversion at all.7
Only when 3,3>-dimethyl-BINOL ((R)-20) was used as the
ligand, did the oxidation go to completion. Lactone 8 having
7 We are grateful to Prof. K.A. Jørgensen (Aarhus University) for a kind donation of (R)-3,3>-bis(2,5-dimethoxyphenyl)-2,2>-dihydroxy-1,1>-
dinaphthyl, which when employed as ligand unfortunately inhibited the Baeyer-Villiger oxidation.
© 2001 NRC Canada

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Can. J. Chem. Vol. 79, 2001
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an (R)-configuration was achieved with an enantiomeric ex-
cess of 40%.8 However, 6,6>-disubstituted BINOL (S)-21
proved to be the most effective ligand, leading to (S)-8 with
77% ee, which is an even higher enantioselectivity than the
one the unsubstituted BINOL ligand induced in the oxidation
of 7.9 Hence, modifications at this end of the BINOL scaffold
with different groups seem to be promising in regards to fur-
ther improvement of the enantioselectivity. We are currently
investigating these BINOL derivatives along with other oxi-
dants and substrates in the aluminum-mediated Baeyer-
Villiger oxidation.
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Experimental
In a typical procedure, a solution of Me2AlCl in hexanes
(0.10 mL, 1.0 M, 0.10 mmol) was injected to enantiopure
BINOL (29 mg, 0.10 mmol; obtained by resolution accord-
ing to ref. 18) in absolute toluene under argon atmosphere.
After stirring for 0.5–1 h at ambient temperature, the ketone
(0.20 mmol) was added to the suspension, which within
15 min at room temperature became less turbid. The mixture
was cooled down to –25°C before the addition of cumene
hydroperoxide (technical grade 80%, 57 mg, 0.30 mmol)
and then slowly let warm to room temperature again. After
12 h of stirring the mixture was treated with aq. HCl (0.5 M),
then diluted with ether, washed with saturated. aq. NaHCO3
and brine, and finally dried over MgSO4. The obtained solu-
tion was directly subjected to GC analysis for the determina-
tion of the conversion (calculated from area percentages in
the GC) and the ee (using chiral columns). The peak assign-
ments were assured by comparison with chromatograms of
ketones and racemic lactones.
For the correlations of optical rotations and absolute con-
figurations, see ref. 10a for 2a, ref. 10b for 2b, ref. 10c for
8, ref. 10d for 10, ref. 7e for 14, and ref. 10e for 16. In
ref. 7a, (R)-configurated 3-pentyl- and 3-hexyl-butyrolactones
were shown to have a positive sign of optical rotation. Thus,
the absolute configuration of octyl-bearing lactone (+)-12 is
supposed to be (R) too.
When isolated yields were to be determined, 1 to 2 mmol
of ketone were employed and the product purified by col-
umn chromatography on silica gel.
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Acknowledgments
We are grateful to the Deutsche Forschungsgemeinschaft
(Schwerpunktprogramm Sauerstofftransfer/Peroxidchemie,
Graduiertenkolleg 440) and the Fonds der Chemischen
Industrie for support of our research program.
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