Preparation of TADOOH, a hydroperoxide from TADDOL, and use in highly enantioface- and enantiomer-differentiating oxidations

Article abstract of DOI:10.1002/1522-2675(20010131)84:1<187::AID-HLCA187>3.0.CO;2-O

Replacement of one OH group in TADDOL ( = a,a,a′,a′-tetraaryl-1,3-dioxolane-4.5-dimethanol) by an OOH group gives a stable, crystalline chiral hydroperoxy alcohol TADOOH ( = [(4R,5R)-5-[(hydroperoxydiphenyl)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl] diphenylmethanol) 3, the crystal structure of which resembles those of numerous other TADDOL derivatives (Fig. 2). The new hydroperoxide was tested as chiral oxidant in three types of reactions: the epoxidation of enones with base catalysis (Scheme 2), the sulfoxidation of methyl phenyl sulfide (Scheme 3), and the Baeyer-Villiger oxidation of bicyclic and tricyclic cyclobutanones, rac-10a-d with kinetic resolution (Scheme 4, Fig. 3, and Table). Products of up to 99% enantiomer purity were isolated (the highest values yet observed for oxidations with a chiral hydroperoxide!). Mechanistic models are proposed for the stereochemical courses of the three types of reactions (Schemes 5 and 6, and Fig. 4). Results of AM1 calculations of the relative transition-state energies for the anionic rearrangements of the exo Criegee adducts of TADOOH to the enantiomeric bicyclo[3.2.0]heptan-6-ones are in qualitative agreement with the observed relative rates (Table and Fig. 5).

Full text of DOI:10.1002/1522-2675(20010131)84:1<187::AID-HLCA187>3.0.CO;2-O

Helvetica Chimica Acta ± Vol. 84 (2001)
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Preparation of TADOOH, a Hydroperoxide from TADDOL,
and Use in Highly Enantioface- and Enantiomer-Differentiating Oxidations
by Masao Aoki1) and Dieter Seebach*
Laboratorium für Organische Chemie der Eidgenössischen Technischen Hochschule Zürich, ETH-Zentrum,
Universitätstrasse 16, CH-8092 Zürich
Replacement of one OH group in TADDOL (ˆa,a,a',a'-tetraaryl-1,3-dioxolane-4,5-dimethanol) by an
OOH group gives a stable, crystalline chiral hydroperoxy alcohol TADOOH (ˆ{(4R,5R)-5-[(hydroperoxy-
diphenyl)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}diphenylmethanol) 3, the crystal structure of which resembles
those of numerous other TADDOL derivatives (Fig. 2). The new hydroperoxide was tested as chiral oxidant in
three types of reactions: the epoxidation of enones with base catalysis (Scheme 2), the sulfoxidation of methyl
phenyl sulfide (Scheme 3), and the Baeyer-Villiger oxidation of bicyclic and tricyclic cyclobutanones, rac-10a ± d
with kinetic resolution (Scheme 4, Fig. 3, and Table). Products of up to 99% enantiomer puritiy were isolated
(the highest values yet observed for oxidations with a chiral hydroperoxide!). Mechanistic models are proposed
for the stereochemical courses of the three types of reactions (Schemes 5 and 6, and Fig. 4). Results of AM1
calculations of the relative transition-state energies for the anionic rearrangements of the exo Criegee adducts of
TADOOH to the enantiomeric bicyclo[3.2.0]heptan-6-ones are in qualitative agreement with the observed
relative rates (Table and Fig. 5).
1. Introduction. ± Besides C,C-bond-forming reactions, oxidations, and reductions/
hydrogenations are the corner stones of organic synthesis. Enantioselective versions of
essentially all synthetic transformations in which chiral products arise from achiral
precursors are now available, and spectacular examples of enantioselective catalysis
continue to appear in the literature. Thus, in the field of oxidations, there are the
Sharpless epoxidation, dihydroxylation, and aminohydroxylation [1], the Julia epox-
idation of enones [2], the Jacobsen-Katsuki epoxidation [3], the Kagan sulfoxidation
[4], and enantioselective Baeyer-Villiger oxidations [5].
On the other hand, the use of chiral hydroperoxides for enantioselective oxidations
has, so far, met with little success2). The chiral hydroperoxides [8 ± 10] and peracids
[11] employed have been obtained by chromatographic resolution [8] or by enzymatic
kinetic resolution [9] of racemic mixtures, or by derivatization of natural products, such
as carbohydrates, with H2O2 [10] (see the Formulae in Fig. 1). It is probably fair to state
that no selectivites above 50% ee (enantioselectivity 75% es) have generally been
obtained in oxidations with chiral hydroperoxides3).
1
)
)
)
Postdoctoral Fellow at ETH-Zürich (1999 ± 2000), under the auspices of the Japan Society for the
Promotion of Science (JSPS).
For enantioselective hydroxylations with chiral dioxiranes and oxaziridines (mainly of enol derivatives),
see [6][7].
For a discussion of enone epoxidations and an example in which 95% es was observed with a special
substrate, see [12].
2
3

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Fig. 1. Some chiral hydroperoxides obtained by chromatographic or enzymatic (kinetic) resolution, or from
suitable chiral precursors and H2O2. Some of these compounds have been tested as stoichiometric reagents for
enone epoxidation [12], for epoxidation of allylic alcohols [8b ± d][14], or for sulfoxidation [8c,d][13]. The
imino-sulfonyl-peracid shown was generated in situ [11].
We now report a new type of chiral hydroperoxide that is readily prepared from
H2O2 and a TADDOL, that can be regenerated after use, and that can be used for
several enantioselective and ꢀenantiodifferentiatingꢁ4) oxidations with selectivities
above 90%5).
2. Results and Discussion. ± 2.1. Preparation and Structure of TADOOH 3.
Substitution reactions with replacement of TADDOL OH groups are facile and
surprisingly clean, considering the fact that they must occur by the Sn1 mechanism, and
that the intermediate cation(s) could undergo various reactions, besides being trapped
by a nucleophile6). Thus, both OH groups of TADDOL 1 are replaced by Cl with
SOCl2 in 82% yield [18], while the Appel reaction stops cleanly at the stage of the
monochloride 2, which is isolated in 72% yield [19]. The subsequent replacement of Cl
by OOH (2 ! 3 in Scheme 1) has been achieved in various ways7). In the simplest
procedure, the urea ´ H2O2 complex is employed in dimethylformamide (DMF)
solution, producing the hydroperoxy alcohol 3 at 508 in almost 90% yield (after
chromatography), on a 15-mm scale. Compound 3 ([a]Dr:t:
ˆ
116.5 in CH2Cl2) is
4
)
)
For the terminology of stereochemistry, see Helmchenꢁs introduction to the Houben-Weyl, Vol. E21a [15].
For the term enantiodifferentiating, see the definitions by Izumi [15][16].
5
We use the terms enantioselectivity (% es), enantiomer ratio (er), and enantiomer purity (% ep), and
avoid enantiomeric excess (% ee); for a list of stereochemical terms not to be used, see [17].
TADDOL Ethers are cleaved under acid catalysis in solutions containing H2O.
Reaction of 2 with a MgSO4-dried solution of H2O2 in THF also leads to formation of 3, which can be
separated chromatographically (SiO2) from accompanying TADDOL 1.
6
7
)
)

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Scheme 1. Preparation of the Hydroperoxide 3 from TADDOL
surprisingly stable under the actual working conditions8). Like TADDOLs9), the
hydroperoxy derivative tends to form inclusion compounds with H-bond acceptors, and
it is not surprising that we obtained crystals suitable for X-ray structure analysis with
DMF as guest molecules (Fig. 2).
As in the structures of all non-symmetrical TADDOL derivatives9) capable of
forming intramolecular H-bonds [20][21], the more acidic XH group (OOH in 3) acts
È
as the H-bond donor and the less-acidic YH group (OH in 3) as the H-bond acceptor:
there is an eight-membered H-bonded ring in the crystal structure of hydroperoxy
alcohol 3; otherwise, the propeller-like arrangement in 3 of two Ph groups (upper right
and lower left side) in a quasi-axial and two in a quasi-equatorial position is the same as
in dozens of other structures of TADDOLs and their derivatives.
2.2. Epoxidation of Enones by TADOOH 3. We first tested the new hydroperoxy
alcohol 3 for epoxidations of enones, and we chose the standard substrate chalcone to
optimize conditions (Scheme 2). This reaction has been carried out previously under
numerous conditions, with achiral and chiral hydroperoxides, by base catalysis10).
We found that treatment of TADOOH 3 with various bases in THF and addition of
1,3-diphenylprop-2-en-1-one at temperatures between 75 and ‡ 208 led to formation
of the epoxy ketone 4 in high yield and with excellent enantioselectivities. Two types of
conditions were found to give the best results. i) Conversion of the hydroperoxide to
the Li salt by treatment with a sub-stoichiometric amount of BuLi and reaction with the
enone at low temperature (Entries 7 ± 15 in Scheme 2): under these conditions,
enantioselectivities of up to 98.5% (GC analysis), with formation of the ( )-
(2R,3S)-epoxy ketone 4, were obtained (Entry 10), the absolute configuration being
assigned by optical comparison [2a]. ii) The need to activate the enone and at the same
time deprotonate the hydroperoxide (to increase its nucleophilicity) was also met by
applying what has been called bifunctional catalysis [22 ± 24] (Entries 12 ± 15 in
Scheme 2): a catalytic amount of LiCl/DBU, a non-self-annihilating Lewis acid/base
pair, gave an enantioselectivity at 08 (Entry 15) comparable to that observed with the
Li peroxide.
8
)
Hydroperoxy alcohol 3 is stable up to ca. 1308 when it begins to melt with decomposition. A dynamic DSC
thermostability test of 3 (carried out at a scan rate of 48/min) showed the beginning of a strong spontaneous
exothermic decomposition reaction above ca. 1308 when ca. 435 kJ/kg are released. This energy would
cause a theoretical adiabatic rise in temperature of ca. 3658 (the estimated heat capacity of the investigated
sample is Cp ˆ 1200 J/(kg ´ K)).
9
)
)
For an extensive review article, covering all aspects of TADDOL chemistry and applications, see [20].
For reviews, see [2f ± i].
10

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Fig. 2. X-Ray crystal structure of the TADOOH ´ DMF inclusion compound 3 ´ OˆCH NMe2. Top : ORTEP
stereoplot with 50% probability level. Bottom: front and top view of the 1:1 complex in an Insight II (version
98.0) presentation. The X-ray analysis included measurement of the Bijvoet pairs, i.e., the absolute
configuration (R,R), as shown here, was determined.
Other enones were also subjected to epoxidation by the new chiral hydroperoxide
in high yield and with variable enantioselectivities (see the epoxy ketones 5 ± 8 in
Scheme 2); these reactions were carried out under the standard TADOOH/BuLi
conditions, and they have not been optimized.
2.3. Sulfoxidation of Methyl Phenyl Sulfide by 3. Another standard substrate for
testing an enantioselective oxidation is methyl phenyl sulfide (MeSPh) [4][25][26].
Besides the sulfoxide 9, there is usually sulfone 10 formed by overoxidation, and there
is the interesting implication that a chiral oxidant will react faster with one of the
enantiomeric sulfoxides than with the other, so that a kinetic resolution of the primarily
formed sulfoxide (which may be cooperative or counterproductive) can complicate
assignment of the enantioselectivity of the actual sulfoxidation step.
As outlined in Scheme 3, TADOOH 3 oxidizes MeSPh without any catalysis. Under
optimized conditions (1.5 equiv. of 3, 3 d at 308 then 1 d at ‡ 208, in THF) the
laevorotatory (S)-sulfoxide 9 is formed in 73% yield, with an enantiomer purity of
93%. Reaction of rac-9 with 3 at room temperature, with 8% conversion to the sulfone
10, leads to recovery of the laevorotatory sulfoxide (S)-9. Thus, the sulfoxide

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Scheme 2. Epoxidation of 1,3-Diphenylprop-2-en-1-one and of Other Enones with Hydrogenperoxy Alcohol 3.
The equivalents of 3 and of the base refer to 1 equiv. of chalcone. The optimization experiments were carried
out with 0.5-mm amounts of chalcone. Enantiomer ratios (er) were determined on chiral GC columns. Yields
after FC are given. The absolute configurations of 4 (2S,3R), 5 (2S,3R), and 7 (2R,3R) as shown in the Formulae
are derived from optical comparison with literature data (see Exper. Part); those of the epoxides 6 and 8 are
tentatively assigned by analogy (see also Sect. 6).
enantiomer that is formed faster in the sulfoxidation step is converted to the sulfone
more slowly (ratio of rates ca. 5 :1). At 308, sulfone formation is negligible (less than
1%).
2.4. Enantiomer-Differentiating Baeyer-Villiger Oxidation of Bicyclic and Tricyclic
Cyclobutanone Derivatives. Another classical peroxide oxidation is the Baeyer-Villiger
reaction converting ketones to esters or lactones [5][27][28]. It is known that, for the
strained cyclobutanones, base-catalyzed oxidative ring enlargement to g-lactones
occurs with H2O2 or RO2H [29], while the normally employed oxidant is a peracid [30].

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Scheme 3. Oxidation of MeSPh by the Hydrogenperoxy Alcohol 3. Reactions were carried out with a 1:1.5
molar ratio of MeSPh and 3. Yields were detected by GC, enantiomer ratios were determined on a chiral GC
column (see Exper. Part).
Baeyer-Villiger reactions also take place in biological systems, catalyzed by peroxidases
[31], and a number of enzymes from various sources have been employed for
enantiomer- or enantiotopos-differentiating oxidations [32]. With racemic mixtures of
cyclobutanone derivatives, the peroxidases (from Acinetobacter or from Cunning-
hamella echinulata) can either induce kinetic resolution [33], or else formation of the
normal lactone from one enantiomer and of the abnormal lactone from the other
[34]11), an enantiomer-differentiating regioselective oxidation12).
For Baeyer-Villiger oxidations with TADOOH 3, we chose cyclobutanones as
substrates, so that we could employ the base-catalysis conditions that worked so well
with the enone epoxidations (vide supra, Sect. 2.2). The cyclobutanones are readily
available by dichloroketene cycloaddition to olefins and subsequent reductive
dechlorination13). Of the rac-cyclobutanones 11a ± d, the unsaturated compound 11c
is commercially available, and hydrogenation gives the saturated bicyclo[3.2.0]hepta-
none 11b (see reference in Exper. Part). Following the literature procedures (see Exper.
Part), we prepared the bicyclo[4.2.0]octanone 11a and the tricyclic derivative 11d from
cyclohexene and norbornene, respectively. Samples of racemic lactones formed as
normal (see 12) and as abnormal (see 13) products of Baeyer-Villiger oxidation were
prepared, and suitable columns for analysis of enantiomer ratios by gas chromatog-
raphy (GC) for the three series of compounds 11, 12, and 13 were chosen. The absolute
configurations of lactones 12a, 12c were assigned by optical comparison with literature
data, the saturated (i.e., 11b, 12b, 13b) and the unsaturated (i.e., 11c, 12c, 13c) series of
11
)
)
Bolm and Schlingloff have shown that a chiral Cu complex exhibits the same behavior when used as a
catalyst in the reaction of rac-cyclobutanone derivatives with O2 in the presence of t-BuCHO [35].
The peroxidases are usually not stable enough to allow for high turnover numbers, so that their use in
organic synthesis has been quite limited [36], in comparison to other types of enzymes (see the two volumes
on Enzyme Catalysis in Organic Synthesis cited in [32a]).
12
13
)
For exhaustive treatises of the chemistry of cyclobutanes, see the corresponding Houben-Weyl volumes
[37][38].

Helvetica Chimica Acta ± Vol. 84 (2001)
193
compounds are correlated by hydrogenation, and, for the tricyclic derivatives (i.e., 11d,
12d, 13d), the assignment is based on analogy (structure analogy, signs of [a]rD:t: ; see
Exper. Part and refs. cit. therein).
For the kinetic resolutions by the enantiomer-differentiating power of TADOOH 3,
we first used the bicyclo[4.2.0]octanone rac-11a as the substrate (see Scheme 4 and
Fig. 3). The reaction is clearly base-catalyzed; without a base, or with the Lewis acid
LiCl alone (Entry 1 in Scheme 4), no reaction took place in THF. With an amount of
BuLi (Entry 2) or DBU/LiCl (Entries 3 ± 5) equivalent to that of the hydroperoxy
alcohol 3, the cyclobutanone was oxidized to give lactone 12a, the normal product
exclusively. The (R,R)-form of 11a reacts faster (by a factor of 15 at 08; see Fig. 3), and,
of course [39], unreacted ketone (S,S)-11a of increasing enantiomer purity can be
recovered with increasing degree of conversion. Thus, with 70% conversion at 308
(DBU/LiCl) the unreacted ketone (S,S)-11a is isolated (26% yield) in an enantiomer
purity of 99%, while the lactone product (R,R)-12a (66% yield) has an enantiomer
purity of 75% (Entry 1 in Scheme 4 and Table). Interestingly, the other three ketones
11b ± d, containing the cyclobutanone ring annelated to a five-membered ring, gave
both the normal (12b ± d) and the abnormal (13b ± d) products of the Baeyer-Villiger
oxidation. Under the standard conditions (as optimized for the bicyclooctanone 11a,
i.e., 70% conversion with DBU/LiCl at 308 in THF), the bicycloheptanone 11b and
bicycloheptenone 11c gave almost identical results: 30% of unreacted ketone (S,S)-11b
and (1R,5S)-11c of 99 and 95% ep and a total of 60 ± 70% of lactones in a 3 :1 ratio of

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Scheme 4. Baeyer-Villiger Oxidation of Bicyclo[4.2.0]octan-7-one by the Hydroperoxy Alcohol 3. The
enantiomer ratio was determined with a chiral GC column (see Exper. Part). Conversions were detected by GC.
normal to abnormal products 12 and 13, with the former consisting mainly (84 and 90%
ep) of the homochiral (R,R)-12b and (1S,5R)-12c and the latter being enantiomerically
pure (ꢀ 99% ep) 13b and 13c, respectively (Entries 2 and 3 in the Table). The tricyclic
ketone 11d reacts somewhat less selectively (Entry 5).
Fig. 3. Enantiomer excess (% ee) of unreacted bicyclooctanone (‡)-(S,S)-11a and of the lactone product ( )-
(R,R)-12a as functions of % conversion in the oxidation of rac-11a with the hydroperoxy alcohol 3 (LiCl/DBU,
THF, 08). The ratio of rates with which (R,R)-11a and (S,S)-11a react with 3 under these conditions is 15 :1
(23 :1 at 758).

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Table. Kinetic Resolution of Bicyclic Cyclobutanone Derivatives by TADOOH 3, DBU, and LiCl. Reactions
were carried out with the ketone, 3, DBU, and LiCl in a 1 : 0.7 : 0.7: 0.7 molar ratio for 1 h at 308. Yields are
given after FC. Enantiomer purity (ep) was determined with a chiral GC column (see Exper. Part).
Entry rac Ketone Unreacted ketone 11
Lactones 12 and 13
Total Ratio
(configuration) yield [%] 12/13
11
mmol
Yield [%] ep [%]
ep of 12 [%] ep of 13 [%]
(conf.)
(conf.)
1
2
3
4
5
a
b
c
c
d
1
2
2
10
1
26
99 (S,S)
99 (S,S)
95 (1R,5S)
90 (1R,5S)
59
66
70
62
64
71
> 99 : 1 75 (R,R)
±
30a)
30
73 : 27
75 : 25
72 : 28
63 : 37
84 (R,R)
90 (1R,5S)
93 (1R,5S)
88
99 (1S,5R)
99 (1S,5R)
99 (1S,5R)
99
26
23
a) Yield determined by GC.
Thus, TADOOH 3 turns out to be an enantiomer-differentiating, and also
regioselective, stoichiometric oxidant in the Baeyer-Villiger reaction of cyclobutanones.
2.5. Mechanistic Considerations. The three oxidations with the chiral hydroper-
oxy alcohol studied by us occur by different mechanisms. All three are well-known
standard reactions of organic synthesis or parts of useful synthetic transforma-
tions (such as a-sulfenylation, sulfoxidation, and elimination for converting carbonyl
compounds to enones or enoates [40 ± 43]), and two of them are name reactions: the
Weitz-Scheffer oxidation of enones by alkaline H2O2 [44], and the Baeyer-Villiger
oxidation of ketones to ester or lactones [27][45]. Besides the numerous applications of
these reactions, there are extensive investigations of their mechanisms to which we will
refer in the following brief discussions of mechanistic models for oxidations with
TADOOH 3.
The so-called epoxidation of electron-deficient olefins can be carried out under a
variety of conditions14). The classical method is treatment with alkaline H2O2 (or
RO2H), and the mechanism consists of a conjugate nucleophilic addition of the peroxy
anion, followed by cyclization in an intramolecular nucleophilic attack of the enolate
formed on the O O bond, as indicated in Scheme 5 for the reaction of an enone. If we
assume that the conjugate addition is the rate- and stereoselectivity-determining
step15), an approach of the lithium peroxide (TADOOLi) to the enone as pictured in
Scheme 5 would lead to formation of the major product(s) observed (see Scheme 2).
The important role played by the counter ion is, of course, not rationalized by this
model: with tert-amines alone, no reaction takes place (R3NH+ counter ion; Entries 2
and 3 in Scheme 2); from KOH through NaOH to LiOH, there is a reversal of the
stereochemical course (30 :70, 45 :55, 80 :20 ratio of enantiomers, Entries 4 ± 6 in
Scheme 2); only with Li+ counterion under totally aprotic conditions do we observe the
highest stereoselectivity (98.5 :1.5).
14
)
)
These include transition-metal and lanthanide catalysis, phase-transfer catalysis, and polypeptide catalysis.
For a recent review article, see [2i].
With this assumption, we follow specialists in the field; see the recent article by Adam et al. [12], and refs.
cit. therein.
15

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7
Scheme 5. Two-Step Mechanism of Enone Epoxidation by RO2 and Mechanistic Model Compatible with the
Stereochemical Outcome of the Epoxidations with TADOOH 3. For conditions, see Scheme 2.
The uncatalyzed sulfoxidation16) by TADOOH 3 (Scheme 3) must be formulated
as nucleophilic attack of the sulfide S-atom on the O O bond as pictured in Fig. 4.
The linear arrangement of S: ± -O O was chosen such that the initially formed
TADDOLate anion would be stabilized by the H-bonding. Minimal van der Waals
interaction is expected with the substituents on sulfone turned away from the neighboring
axial Ph group, and the smaller substituent (Me) near an equatorial Ph group17).
Fig. 4. Mechanistic model rationalizing preferential formation of (S)-methyl phenyl sulfoxide (9) from methyl
17
phenyl sulfide, and TADOOH 3, as well as faster ꢀoveroxidationꢁ to the sulfone 10 of (R)-sulfoxide
)
The Baeyer-Villiger oxidation of ketones is a two-step reaction in which the
hydroperoxide or peracid first adds to the CˆO group to give a tetrahedral
intermediate (Criegee adduct [47][48]) that then undergoes rearrangement to the
16
)
)
For articles on ꢀasymmetric sulfoxidationꢁ with seminal referencing, see [4d][13][46].
Disregarding polar effects and H-bonding effects in the oxidation of the sulfoxide 9 to the sulfone 10, the O-
atom would have to be considered smaller than the Me group (see the right-hand side of Fig. 4).
17

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197
ester or lactone18). Both the formation of the tetrahedral intermediate and the
rearrangement are catalyzed by acid and by base, and either step may be rate-
determining. Without detailed kinetic measurements, as in the present case, a
mechanistic discussion is bound to be rather speculative19). For the reactions of the
cyclobutanones with TADOOH 3, we make the following assumptions: i) the Criegee
adducts are formed rapidly (cyclobutanones are highly reactive carbonyl com-
pounds13)20); ii) only the exo-adducts (cf. diastereoisomers A and B in Scheme 6)
are considered (TADOO is a very bulky peroxy group9); iii) the product-determining
step is the base-catalyzed rearrangement, as depicted in C and D21)22) for the normal
and abnormal routes starting from bicycloheptanone 11b; iv) under the conditions
specified in the Table, the (R,R,R,R)-adduct B reacts ca. 15 times faster than the
(R,R,S,S)-form, and the approximate product distribution after 70% conversion is as
shown in Scheme 6.
We were unable to rationalize the observed product distribution by simple
inspections of models of the Criegee intermediates A and B, for each of which two
preferred conformations must exist, leading to the normal and abnormal products
(S,S)-12b/(R,R)-12b and (1S,5R)-13b/(1R,5S)-13b, respectively. Thus, we calculated
the geometries of lowest free energy of activation DG= for the four anionic22
) ) )
23 24
transition states, using Dewarꢁs semiempirical AM1 method [54]. The resulting
numbers, shown in Fig. 5, are qualitatively in agreement with the experimental results:
the two major products (R,R)-12b and (1S,5R)-13b correspond to the lowest activation
energies, and the minor products (S,S)-12b and (1R,5S)-13b to the higher ones.
3. Concluding Remarks. ± In the era of enantioselective catalysis25), it may look
like a step backwards to study stoichiometric oxidations by a chiral hydroperoxide: the
products obtained (epoxides of enones, sulfoxides, g-lactones) are, indeed, also
accessible in high enantiomer purities by catalytic processes, with H2O2, hydro-
peroxides, peroxides (including dioxiranes), peracids, or O2 and chiral catalysts
18
)
Formally, a sigmatropic 1,2-shift (or a sextett-rearrangement) to an electron-pair-deficient O-center, with
retention of configuration on a migrating stereogenic center, see general textbooks of Organic Chemistry
and [5][28b].
19
20
21
22
)
)
)
)
For an excellent treatise about all mechanistic aspects of the Baeyer-Villiger reaction, see the ꢀminireviewꢁ
by Renz and Meunier [28b].
Simple mixing of 3 with rac-11c in (D8)-THF at ambient temperature does not lead to a Criegee adduct,
1
according to H-NMR analysis.
Maximum stereoelectronic assistance [49 ± 51] is assumed in C and D, with the three breaking bonds
parallel.
Of course, the deprotonation and the C C bond shift need not be concerted: an additional intermediate
would then be the deprotonated Criegee adduct with an O7 group on the cyclobutanone ring. Such an
intermediate is used for AM1 calculations (see Fig. 5).
23
24
)
)
For calculations of the transition-state structure of the Baeyer-Villiger rearrangement of acetone with
performic acid, see [53].
For rearrangement of the neutral Criegee adducts A and B, much higher free energies (ꢀ15 kcal/mol) of
activation are calculated for the formation of the four lactones. The results of our calculations should be
considered with due caution, because they have been performed with anionic transition states, not including
the counter-ion Li+.
25
)
A recent issue of Acc. Chem. Res. was dedicated to the topic ꢀenantioselective catalysisꢁ and contains two
lucid editorials [55].

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Scheme 6. The Two Diastereoisomeric Criegee Intermediates A and B, the Yields of Normal and Abnormal
Products of Baeyer-Villiger Oxidation after 70% Conversion, and Two Geometries C and D for Normal and
Abnormal Rearrangement of (S,S)-11b under Stereoelectronic Control. The numbers for the relative rates with
which the enantiomers (R,R)-11b and (S,S)-11b react are taken from the Table.
(including peptides and enzymes; see the literature cited in the Introduction and in
Sect. 2.5). However, in these catalytic transformations chiral peroxy compounds are
formed in situ, and often in tiny amounts to evade identification, so that the detailed
mechanisms of their action are very difficult to elucidate (cf. the Sharpless epoxidation
of allylic alcohols by t-BuOOH/diethyl tartrate/Ti(OCHMe2)4 [1a ± c]); the same is true
of biological processes in which peroxides play an important role. Thus, studies with
isolable chiral peroxides of well-defined structures, such as TADOOH 3, can be
instrumental in deepening our understanding of mechanistic details of such oxidations,
and it is hoped that the results described here are a step towards this goal. The hitherto
reported enantioselectivities of stoichiometric oxidations by chiral peroxides are
mostly too low to justify meaningful mechanistic interpretations (a 75 :25 ratio of
products at 300 K corresponds to a difference DEa between two competing transition
states of first-order reactions of merely 0.65 kcal/mol!), and much higher values, such

Helvetica Chimica Acta ± Vol. 84 (2001)
199
Fig. 5. Geometries and relative free energies for transition states of the anionic (base catalyzed) rearrangement of
the Criegee adducts A and B (cf. Scheme 6) with formation of the normal (i.e., 12b) and of the abnormal (i.e.,
13b) lactones as calculated by the AM1 software package Spartan [52]. The transition state of lowest energy
((R,R)-10b7 ! (R,R)-11b ‡ TADDOLate7) is arbitrarily set equal to zero.
as some of those observed with TADDOH 3, are a promising prerequisite for valid
mechanistic conclusions. More work is, however, required to start interpretations
beyond the simple models proposed here.

200
Helvetica Chimica Acta ± Vol. 84 (2001)
We thank the Japanese Society for the Promotion of Science for a stipend granted to M.A. We thank Dr. V.
Gramlich for the determining the X-ray crystal structure of 3, and Novartis Pharma AG, Basel, for continuing
financial support, and for a safety test of TADOOH.
Experimental Part
1. General. Abbreviations: DBN: 1,5-diazabicyclo[4.3.0]non-5-ene, DBU: 1,8-diazabicyclo[5.4.0]undec-7-
ene, DMAP: 4-(dimethylamino)pyridine, FC: flash chromatography, UHP: urea/hydrogen peroxide adduct, tR:
retention time, er: enantiomer ratio, % es: enantioselectivity, percent of the major enantiomer formed, % ep:
enantiomer purity, percent of the major enantiomer in a non-racemic mixture. THF (for epoxidation of enone)
was freshly distilled over K under Ar before use. DMF was distilled over CaH2 (Fluka), Et3N over NaOH
(Fluka). Et2O was distilled over NaOH and FeSO4 (Fluka). LiCl (Fluka) was dried at 1508 before use. AcOH,
bicyclo[2.2.1]hept-2-ene, BuLi (1.6m in hexane), CCl4, CH2Cl2, 1,3-diphenylprop-2-en-1-one, cyclohexene,
cyclohex-2-en-1-one, DBU, DMAP, AcOEt, hexane, KOH, LiOH, 3-methylcyclohex-2-en-1-one, MeSPh,
NaOH, pentane, Pd/C, (E)-4-phenylbut-3-en-2-one, pyridine, Ph3P, THF (for sulfoxidation and Baeyer-Villiger
oxidation), Cl3CCOCl, UHP, and Zn (powder) were used as purchased from Fluka, DBN as purchased from
Bayer, bicyclo[3.2.0]hept-2-en-6-one and 30% H2O2 as purchased from Merck, H2 gas as purchased from
GasPan. 1-(Cyclohex-1-enyl)ethanone was used as purchased from Aldrich. TADDOL 1 [18] and the
monochloride 2 [19] were prepared according to literature procedures. Bicyclo[4.2.0]octan-7-one [56] and exo-
tricyclo[4.2.1.02,5]nonan-3-one [57] were obtained from the corresponding olefins (cyclohexene and norbornene
(ˆ bicyclo[2.2.1]hept-2-ene)) by [2 ‡ 2] cycloaddition of dichloroketene (generated in situ from Cl3CCOCl and
Zn powder, with ultrasound activation, according to literature procedures [58]), followed by dechlorination (Zn
powder and AcOH [59]). Bicyclo[3.2.0]heptan-6-one [60] was obtained from bicyclo[3.2.0]hept-2-en-6-one by
catalytic hydrogenation (H2, atmospheric pressure, 10% Pd/C, AcOEt [34]). All long-time reactions at 788
were carried out using a Lauda Ultra Kryomat ꢂ RUK90, all long-time reactions at 308 with a Frigomix ꢂ S.
TLC: Macherey-Nagel Alugram ꢂ SIL G/UV254 or Merck 60F254 silica-gel plates; detection by UV254 nm light or I2,
or by dipping in/spraying with phosphomolybdic acid solution (phosphomolybdic acid (25 g), Ce(SO4)2 ´ 4 H2O
(10 g), H2SO4 (60 ml), H2O (940 ml)). FC: Fluka silica gel 60 (40 ± 63 mm), at ca. 0.3 bar. GC: GC 8000TOP (CE
Instruments); column: Alpha Dex 120, 30 m  0.25 mm (Supelco) or Beta Dex 120, 30 m  0.25 mm (Supelco);
injection temp. 2008, detection temp. 2508, split ratio 26 :1, pressure 100 kPa H2. M.p.: Büchi-510 apparatus,
uncorrected. Optical rotations: Perkin-Elmer 241 polarimeter (10 cm, 1 ml cell), at r.t. IR spectra: Perkin-Elmer
1620-FT-IR spectrometer, in cm 1. NMR Spectra: Bruker AMX 400 (1H: 400 MHz, 13C: 100 MHz), Varian
Gemini 300 (1H: 300 MHz,13C: 75 MHz) or Gemini 200 (1H: 200 MHz, 13C: 50 MHz); chemical shifts (d) in ppm
downfield from TMS (d ˆ 0.0) as internal standard; J values in Hz; unless otherwise stated, CDCl3 solutions.
MS: Finnigan MAT-TSQ 7000 (ESI) spectrometer; in m/z (% of basic peak). Elemental analyses were
performed by the Microanalytical Laboratory of the Laboratorium für Organische Chemie, ETH Zürich.
2. Preparation of {(4R,5R)-5-[Hydroperoxydiphenyl)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}diphenyl-
methanol (TADOOH 3). A 50-ml, dry two-necked round-bottomed flask containing a Teflon-coated stirring
bar was charged with 2 (8.00 g, 14.6 mmol), UHP (24.0 g, 164 mmol), and anh. DMF (60 ml) under Ar. The
colorless soln. was stirred for 24 h at 508. The resulting heterogeneous mixture was filtered, and washed with
H2O and pentane to give 10.47 g of crude product, which was dissolved in CH2Cl2 and washed twice with H2O,
dried (Na2SO4), and chromatographed (50 g of SiO2, CH2Cl2). The solvent was evaporated under reduced
pressure to give a colorless amorphous material, which was triturated with hexane (20 ml) for 10 min at r.t. to
yield 3 (6.88 g, 14.3 mmol, 87%). M.p. 142 ± 1438 (dec.)8). Rf 0.49 (CH2Cl2). [a]rD:t:
[a]rD:t:
1672, 1601, 1495, 1447, 1382, 1166, 1079, 1053, 1033, 1013, 885, 644, 600. 1H-NMR (300 MHz): 0.63 (s, Me); 0.93
(s, Me); 3.57 (s, OH); 5.04 (d, J ˆ 7.2, CH); 5.14 (d, J ˆ 7.2, CH); 7.23 ± 7.51 (m, 20 arom. H); 9.66 (s, OOH).
13C-NMR (75 MHz): 27.15 (Me); 27.62 (Me); 77.81; 79.77; 81.17; 89.57; 110.81; 127.03; 127.33; 127.41; 127.58;
127.66; 127.75; 127.90; 128.30; 128.58; 128.93; 129.42; 139.74; 142.36; 143.20; 145.90. Anal. calc. for C31H30O5
(482.58): C 77.16, H 6.27; found: C 76.98, H 6.41.
ˆ
116.5 (c ˆ 1.0, CH2Cl2);
ˆ
135.2 (c ˆ 1.0, MeOH). IR (CHCl3) 3673, 3578, 3462, 3299, 3089, 3062, 2935, 2874, 1956, 1891, 1813,
3. Enantioselective Epoxidation of 1,3-Diphenylprop-2-en-1-one at 788. General Procedure 1 (GP 1). A
dry 10-ml Schlenk tube containing a Teflon-coated stirring bar was charged with 3 (180.9 mg, 0.375 mmol), base
(Scheme 2, Entries 2 ± 10; 0.275 mmol) or LiCl/tert-amine (LiCl (0.275 mmol, 11.9 mg), tert-amine
(0.275 mmol); Scheme 2, Entries 11 ± 15), and THF (1.0 ml) under Ar. The mixture was cooled to 788, then
1,3-diphenylprop-2-en-1-one (52.1 mg, 0.25 mmol) in THF (0.5 ml) was added. The mixture was stirred at 788

Helvetica Chimica Acta ± Vol. 84 (2001)
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for 3 h, at 08 for 2.5 h, and at r.t. for 1 h. The resulting yellow soln. was combined with sat. NH4Cl soln. (0.5 ml),
stirred for 10 min at r.t., and extracted three times with Et2O. The combined org. phases were dried (Na2SO4),
and the solvent was evaporated under reduced pressure. The residue was purified by FC (30 g of SiO2; hexane/
Et2O 5 :1) to yield 4 as colorless oil. The er was determined by GC analysis. GC (column: Alpha Dex 120,
30 m  0.25 mm; column temp., 1808: tR ((2S,3S)-4) 41.1 min; tR ((2R,3R)-4) 42.2 min.
4. Enantioselective Epoxidation of a,b-Enones at 308. General Procedure 2 (GP 2). A dry 10-ml Schlenk
tube containing a Teflon-coated stirring bar was charged with 3 (361.9 mg, 0.75 mmol) and THF (1.5 ml) under
Ar. The mixture was cooled to 308, then BuLi (1.6m, 0.34 ml, 0.55 mmol) was added (cf. Entries 7 ± 10 in
Scheme 2). After 10-min stirring, the enone (0.50 mmol) in THF (0.5 ml) was added. The mixture was stirred for
1 d at 308. The resulting yellow soln. was combined with sat. NH4Cl soln. (0.5 ml), stirred for 10 min at r.t., and
extracted three times with Et2O. The combined org. phases were dried (Na2SO4), and the solvent was
evaporated under reduced pressure. The residue was purified by FC or bulb-to-bulb distillation.
(2S,3R)-2,3-Epoxy-1,3-diphenylpropan-1-one (4). (E)-1,3-Diphenylprop-2-en-1-one (104 mg, 0.50 mmol)
was allowed to react with 3 in the presence of BuLi, according to GP 2. The crude product was purified by FC
(30 g of SiO2; pentane/Et2O 5 :1) to yield 4 (110.5 mg, 0.49 mmol, 98%) as colorless oil; 95% es (GC analysis).
GC (column: Alpha Dex120, 30 m  0.25 mm; column temp, 1808: tR ((2R,3S)-4 (minor)) 41.0 min; tR ((2S,3R)-4
(major)) 42.2 min. [a]Dr:t: ˆ ‡209.0 (c ˆ 0.86, CH2Cl2) ([2a][61]: (2R,3S)-4: [a]Dr:t:
ˆ
214 (c ˆ 2.72, CH2Cl2)).
1H-NMR (300 MHz): 4.06 (d, J ˆ 1.9, CH); 4.29 (d, J ˆ 1.9, CH); 7.35 ± 7.39 (m, 5 arom. H); 7.43 ± 7.49
(m, 2 arom. H); 7.57 ± 7.63 (m, 1 arom. H); 7.97 ± 7.99 (m, 1 arom. H); 8.00 ± 8.01 (m, 1 arom. H). 13C-NMR
(75 MHz): 59.26 (OCH); 60.86 (OCH); 125.68; 128.22; 128.66; 128.77; 128.95; 133.90; 135.31; 135.34; 192.95
(CˆO). All anal. data were in accordance with the literature values [62].
(3S,4R)-3,4-Epoxy-4-phenylbutan-2-one (5). (E)-4-Phenylbut-3-en-2-one (146.2 mg, 1.0 mmol) was al-
lowed to react with 3 in the presence of BuLi, according to GP 2. Crude product was purified by bulb-to-bulb
distillation (123 ± 1258/11 Torr) to yield 5 (120.0 mg, 0.74 mmol, 74%) as colorless oil; 89% es (GC analysis). GC
(column: Beta Dex 120, 30 m  0.25 mm; initial column temp, 1108 (15 min); heating rate, 58/min (to 1508)): tR
((3S,4R)-5 (major)) 23.9 min; tR ((3R,4S)-5 (minor)) 24.1 min. [a]rD:t: ˆ ‡70.2 (c ˆ 1.0, CHCl3) ([63]: (3S,4R)-5
[a]Dr:t: ˆ ‡75.5 (c ˆ 2.2, CHCl3, 98% ee)). 1H-NMR (300 MHz): 2.19 (s, Me); 3.49 (d, J ˆ 1.9, OCH); 4.00 (d, J ˆ
1.9, OCH); 7.26 ± 7.38 (m, 5 arom. H); 9.66 (s, 1 H). 13C-NMR (75 MHz): 24.82 (Me); 57.85 (CO); 63.60 (CO);
125.97; 128.97; 129.30; 135.32; 204.14 (CˆO). All anal. data were in accordance with the literature values [64].
1-(1,2-Epoxycyclohexyl)ethanone (6). 1-(Cyclohex-1-enyl)ethanone (62.1 mg, 0.50 mmol) was allowed to
react with 3 in the presence of BuLi, according to GP 2. Crude product was purified by FC (15 g of SiO2;
pentane/Et2O 3 :1) followed by bulb-to-bulb distillation (42 ± 438/2.5 Torr) to yield 56.5 mg of a 47:53 mixture of
starting material (1-(cyclohex-1-enyl)ethanone, 24.8 mg, 0.20 mmol, 40%) and 6 (31.7 mg, 0.23 mmol, 46%) as
colorless oil; 70% es (GC analysis). GC (column: Beta Dex 120, 30 m  0.25 mm; initial column temp, 808
(10 min); heating rate, 28/min (to 1508)): tR(6 (minor)) 20.6 min; tR (6 (major)) 21.6 min. The optical activity of
the mixture (calculated for the concentration of 6) was [a]Dr:t:
ˆ
9.5 (c ˆ 0.21, CHCl3). 1H-NMR (300 MHz) of
6: 1.21 ± 1.54 (m, 4 H); 1.62 ± 1.93 (m, 2 H); 2.05 (s, Me); 1.92 ± 2.31 (m, 1 H); 2.47 ± 2.61 (m, 1 H); 3.29 ± 3.31
(m, OCH). 13C-NMR (75 MHz) of 6: 18.84; 19.36; 22.12; 23.34; 24.34; 57.02 (OCH); 63.10 (OC); 208.62
(OˆC). The spectroscopic data were in accordance with the literature values [65].
(R,R)-2,3-Epoxycyclohexan-1-one (7). Cyclohex-2-en-1-one (96.1 mg, 1.0 mmol) was allowed to react with
3 in the presence of BuLi, following GP 2. Crude product was purified by FC (30 g of SiO2 ; pentane/Et2O 3 :1)
followed by bulb-to-bulb distillation (70 ± 808/10 Torr) to yield 7 (50.0 mg, 0.45 mmol, 45%) as colorless oil;
55% es (GC analysis). GC (column: Beta Dex 120, 30 m  0.25 mm, initial column temp., 808 (2 min); heating
rate, 28/min (to 1008)): tR ((S,S)-7 (minor)) 13.4 min; tR ((R,R)-7 (major)) 13.6 min. [a]rD:t: ˆ ‡6.6 (c ˆ 1.0,
MeOH) ([66]: (R,R)-7: [a]rD:t: ˆ ‡90.5 (c ˆ 0.60, MeOH; 87.5% es)). 1H-NMR (300 MHz): 1.65 ± 1.73 (m, 1 H);
1.83 ± 2.14 (m, 3 H); 2.23 ± 2.31 (m, 1 H); 2.51 ± 2.59 (m, 1 H); 3.22 (d, J ˆ 4.0, CH); 3.58 ± 3.61 (m, CH).
13C-NMR (75 MHz): 16.94; 22.79; 36.31; 55.06 (OCH); 55.89 (OCH); 205.98 (CˆO). The anal. data were in
accordance with the literature values [62].
3-Methyl-2,3-epoxycyclohexan-1-one (8). 3-Methylcyclohex-2-en-1-one (55.1 mg, 0.50 mmol) was allowed
to react with 3 in the presence of BuLi, according to GP 2. Crude product was purified by FC (15 g of SiO2;
pentane/Et2O 5 :1), followed by bulb-to-bulb distillation (60 ± 658/5 Torr) to yield 8 (46.6 mg, 0.37 mmol, 74%)
as colorless oil; 91% es (GC analysis). GC (column: Beta Dex 120, 30 m  0.25 mm; column temp, 1008): tR (8
(minor)) 8.7 min; tR (8 (major)) 9.3 min. [a]rD:t: ˆ ‡101.0 (c ˆ 1.0, MeOH) ([66]: [a]rD:t:
ˆ
122.6 (c ˆ 0.51,
MeOH)). 1H-NMR (300 MHz): 1.46 (s, Me); 1.61 ± 1.68 (m, 1 H); 1.82 ± 2.16 (m, 4 H); 2.45 ± 2.55 (m, 1 H); 3.08
(s, CH). 13C-NMR (75 MHz): 17.11; 22.17; 28.33; 35.63; 61.94 (OCH); 62.37 (OC); 206.75 (CˆO). The NMR
data were in accordance with the literature values [62].

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5. Enantioselective Sulfoxidation of MeSPh. (S)-Methyl Phenyl Sulfoxide (9). A 10-ml round-bottomed
flask containing a Teflon-coated stirring bar was charged with 3 (180.9 mg, 0.35 mmol) and THF (1.5 ml). The
mixture was cooled to 308, then MeSPh (31.1 mg, 0.25 mmol) was added. This mixture was stirred for 3 d at
308 then for 1 d at r.t. The solvent was evaporated under reduced pressure. The residue was purified by FC
(15 g of SiO2; Et2O) to yield 9 (25.5 mg, 0.18 mmol, 73%) as a colorless oil; 93% es (GC analysis). GC (column:
Alpha Dex 120, 30 m  0.25 mm; initial column temp, 1108 (40 min); heating rate, 28/min (to 1508)): tR ((S)-9
(major)) 30.7 min; tR ((R)-9 (minor)) 31.4 min. [a]Dr:t:
ˆ
154.8 (c ˆ 2.1, CHCl3) ([67]: (S)-9: [a]Dr:t:
ˆ
131.0
(c ˆ 0.53, CHCl3 , 81% ee)). 1H-NMR (300 MHz): 2.73 (s, Me); 7.50 ± 7.57 (m, 3 arom. H); 7.63 ± 7.68
(m, 2 arom. H). 13C-NMR (75 MHz): 43.91 (Me); 123.43; 129.31; 130.97; 145.66. The spectroscopic data were
in accordance with the literature values [26c].
6. Kinetic Resolution of rac-Methyl Phenyl Sulfoxide (9). A 10-ml round-bottomed flask containing a
Teflon-coated stirring bar was charged with 3 (24.1 mg, 0.050 mmol), rac-9 (35.1 mg, 0.25 mmol), and THF
(1 ml). The mixture was stirred for 7 h at r.t. An aliquot was withdrawn from the mixture and analyzed by GC:
8% conversion and 53% ep (9). GC (column: Alpha Dex 120, 30 m  0.25 mm; initial column temp, 1108
(40 min); heating rate, 28/min (to 1508)): tR ((S)-9 (major)) 30.7 min; tR ((R)-9 (minor)) 31.4 min; tR (10)
48.5 min.
7. Kinetic Resolution of Bicyclo[4.2.0]octan-7-one at 08. A 25-ml, round-bottomed flask containing a Teflon-
coated stirring bar was charged with rac-bicyclo[4.2.0]octan-7-one (0.15 mmol), DBU (27.4 mg, 0.18 mmol),
LiCl (7.6 mg, 0.18 mmol), and THF (15 ml). The mixture was cooled to 08, 3 (92.0 mg, 0.18 mmol) was added in
eight portions (each 11.5 mg, 0.0225 mmol) every 30 min. After each addition, a small sample of the mixture was
withdrawn by syringe, quenched with sat. NH4Cl/hexane, and analyzed by GC. The results are shown in
Scheme 4 and in Fig. 3.
8. Kinetic Resolution of Cyclobutanone Derivatives. General Procedure 3 (GP 3). A 25-ml, round-bottomed
flask containing a Teflon-coated stirring bar was charged with cyclobutanone derivative (1.0 mmol), DBU
(106.6 mg, 0.70 mmol), LiCl (29.7 mg, 0.70 mmol), and THF (15 ml). The mixture was cooled to 308, then 3
(337.8 mg, 0.70 mmol) was added, and stirring was continued at 308 for 1 h. The resulting soln. was combined
with sat. NH4Cl soln. (15 ml), stirred for 10 min at r.t., extracted with Et2O (4 Â 10 ml). The combined org.
phases were dried (Na2SO4), and the solvent was evaporated under reduced pressure. The residue was purified
by FC.
8.1. Kinetic Resolution of Bicyclo[4.2.0]octan-7-one: (S,S)-Bicyclo[4.2.0]octan-7-one (11a) and (R,R)-7-
Oxabicyclo[4.3.0]nonan-8-one (12a). rac-Bicyclo[4.2.0]octan-7-one (124.2 mg, 1.0 mmol) was allowed to react
with 3 in the presence of DBU and LiCl, according to GP 3. The crude product was purified by FC (15 g of SiO2;
hexane/Et2O 10 :1 ! 5 :1 ! 1:2) to yield 11a (32.7 mg, 0.263 mmol, 26.3% yield) and 12a (92.5 mg, 0.660 mmol,
66.0% yield) as colorless oils.
Data of 11a: 99% ep (GC analysis). GC (column: Beta Dex 120, 30 m  0.25 mm; initial column temp., 858
(25 min); heating rate, 108/min (to 1508)): tR ((R,R)-11a (minor)) 22.8 min; tR ((S,S)-11a (major)) 23.3 min.
[a]Dr:t: ˆ ‡18.1 (c ˆ 1.00, CHCl3). 1H-NMR (300 MHz): 1.04 ± 1.28 (m, 3 H); 1.37 ± 1.59 (m, 3 H); 1.94 ± 1.98
(m, 1 H); 2.12 ± 2.18 (m, 1 H); 2.43 ± 2.52 (m, 2 H); 3.10 ± 3.19 (m, 1 H); 3.25 ± 3.30 (m, 1 H).13C-NMR
(100 MHz): 21.06; 22.21; 22.34; 22.43; 29.32; 52.02; 56.55; 210.19 (CˆO). Anal. data were in accordance with
the literature values [56]. Judging from the absolute configuration of 12a formed in this kinetic resolution, the
abs. configuration of 11a must be (S,S).
Data of 12a: 75% ep (GC analysis). GC (column: Beta Dex 120, 30 m  0.25 mm; initial column temp., 858
(25 min); heating rate, 108/min (to 1508)): tR ((R,R)-12a (major)) 36.4 min; tR ((S,S)-12a (minor)) 36.7 min.
[a]rD:t: ˆ ‡29.1 (c ˆ 1.00, CHCl3) ([68]: (S,S)-12a: [a]Dr:t:
ˆ
40.3 (c ˆ 8, CHCl3)). 1H-NMR (300 MHz): 1.23 ±
1.31 (m, 2 H); 1.43 ± 1.55 (m, 2 H); 1.62 ± 1.77 (m, 3 H); 2.03 ± 2.12 (m, 1 H); 2.24 (dd, J ˆ 2.6, 16.8, OˆCH);
2.34 ± 2.44 (m, CH); 2.62 (dd, J ˆ 6.8, 16.8, OˆCH); 4.52 (dt, J ˆ 4.1, 4.4, OCH). 13C-NMR (100 MHz): 19.53;
22.45; 26.78; 27.43; 34.50; 37.15; 78.83 (OCH); 177.31 (CˆO). All anal. data were in accordance with the
literature values [68].
8.2. Kinetic Resolution of Bicyclo[3.2.0]heptan-6-one: (S,S)-Bicyclo[3.2.0]heptan-6-one (11b), (R,R)-2-
Oxabicyclo[3.3.0]octan-3-one (12b), and (1S,5R)-3-Oxabicyclo[3.3.0]octan-2-one (13b). rac-Bicyclo[3.2.0]-
heptan-6-one (220.3 mg, 2.0 mmol) was allowed to react with 3 in the presence of DBU and LiCl, following
GP 3. A small aliquot of the mixture was withdrawn and analyzed by GC to provide the degree of conversion;
after 70% conversion, the crude product was isolated and purified by FC (30 g of SiO2; hexane/Et2O 10 :1 !
5 :1 ! 1:2) to yield a 2 :1 mixture 12b/13b (174.8 mg, 1.39 mmol, 69.5% yield) as a colorless oil, as well as a soln.
of 11b. Because of its volatility, 11b was not separated from the solvent. The isomeric lactones 12b and 13b could

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not be separated by FC. Thus, their mixture was analyzed on a chiral column to afford the ratio of (R,R)-12b/
(S,S)-12b/(1S,5R)-13b/(1R,5S)-13b. For configurational assignments, as given here, see Sect. 9.
Data of 11b: 99% ep (GC analysis). GC (column: Beta Dex 120, 30 m  0.25 mm; column temp, 858): tR
((R,R)-11b (minor)) 10.3 min; tR ((S,S)-11b (major)) 10.6 min. 1H-NMR (300 MHz): 1.50 ± 1.92 (m, 5 H);
2.02 ± 2.06 (m, 1 H); 2.49 (ddd, J ˆ 3.4, 4.4, 18.4, OˆCH); 2.84 ± 2.94 (m, CH); 3.19 (ddd, J ˆ 4.4, 8.4, 9.3,
OˆCH); 3.51 ± 3.59 (m, CH). 13C-NMR (100 MHz): 24.60; 28.79; 29.70; 51.44; 64.79 (CH); 214.91 (CˆO). The
spectroscopic data were in accordance with the literature values [61].
Data of 12b/13b: 12b: 84% ep, 13b: 99% ep (GC analysis). GC (column: Alpha Dex 120, 30 m  0.25 mm;
column temp, 958): tR ((R,R)-12b (major)) 30.7 min; tR ((S,S)-12b (minor)) 31.0 min; tR ((1S,5R)-13b (major))
28.6 min; tR ((1R,5S)-13b (minor)) 29.0 min. The optical activity of the mixture of lactones 12b and 13b was
[a]Dr:t: ˆ ‡45.6 (c ˆ 1.00, CHCl3). The literature values are [a]Dr:t:
ˆ
59 (c ˆ 1, MeOH) for (S,S)-12b [69], and
[a]rD:t: ˆ ‡96.9 (c ˆ 1, CHCl3) for (1S,5R)-13b [70]; if we assume that the specific rotation of 12b in MeOH and in
CHCl3 do not differ a lot, we can calculate the [a]rD:t: value for the mixture of 12% (S,S)-12b ‡ 61% (R,R)-12b ‡
27% (1S,5R)-13b ‡< 1% (1R,5S)-13b (cf. Table and Scheme 6) to be ‡ 558, which is not very different from the
measured value ‡ 45.68.
The NMR spectrum of the 12b/13b mixture could be interpreted, and all the signals assigned by comparison
with the spectrum of rac-12b (90%)/rac-13b (10%), as obtained from rac-11b and m-chloroperbenzoic acid.
1H-NMR (300 MHz): 12b: 1.52 ± 2.08 (m, 6 H); 2.29 (dd, J ˆ 1.6, 17.1, OˆCCH); 2.86 ± 2.89 (m, 2 H); 5.01
(m, OCH); 13b: 1.51 ± 3.00 (m, 8 H); 3.94 (dd, J ˆ 3.1, 9.3, OCH); 4.47 (dd, J ˆ 7.8, 9.3, OCH). 13C-NMR
(100 MHz): 12b: 23.24; 33.32; 33.45; 35.89; 37.75; 86.29 (CO); 177.71 (CˆO); 13b: 25.34; 30.55; 33.61; 38.79;
44.34; 73.51 (CO); 181.03 (CˆO). These data were in accordance with literature values reported for 12b [71]
and 13b [70].
8.3. Kinetic Resolution of Bicyclo[3.2.0]hept-2-en-6-one: (1R,5S)-Bicyclo[3.2.0]hept-2-en-6-one (11c),
(1R,5S)-2-Oxabicyclo[3.3.0]oct-6-en-3-one (12c), and (1S,5R)-3-Oxabicyclo[3.3.0]oct-6-en-2-one (13c). rac-
Bicyclo[3.2.0]hept-2-en-6-one (1.08 g, 10 mmol) was allowed to react with 3 in the presence of DBU and LiCl,
according to GP 3. The crude product was purified by FC (100 g of SiO2; pentane/Et2O 10 :1 ! 5 :1 ! 1 :2) to
yield 11c (275.4 mg, 2.55 mmol, 25.5%) as a colorless oil and a 7:3 mixture 12c/13c (not separable by FC;
797.2 mg, 6.42 mmol, 64.2%) as a colorless oil.
Data of 11c: 90% ep (GC analysis); for assignment of abs. configuration, see Sect. 9. GC (column: Beta
Dex 120, 30 m  0.25 mm; initial column temp, 858): tR ((1S,5R)-11c (minor)) 8.5 min; tR ((1R,5S)-11c (major))
8.9 min. [a]Dr:t: ˆ ‡34.7 (c ˆ 1.00, CH2Cl2). 1H-NMR (300 MHz): 2.84 (dddd, J ˆ 1.9, 4.1, 9.7, 17.4, OˆCCH);
2.65 ± 2.75 (m, 2 H); 3.33 (ddd, J ˆ 2.9, 8.4, 17.4, CˆCCH); 3.44 ± 3.53 (m, 1 H); 3.84 ± 3.92 (m, 1 H); 5.78 ± 5.81
(m, CˆCH); 5.83 ± 5.87 (m, CˆCH). 13C-NMR (100 MHz): 34.82; 36.77; 54.20; 61.84; 132.17 (CˆC); 132.80
(CˆC); 213.18 (CˆO). The spectroscopic data were in accordance with the literature values [72].
Data of 12c/13c: 12c: 93% ep; 13c: 99% ep (GC analysis); for assignment of abs. configuration, see Sect. 9.
GC (column: Alpha Dex 120, 30 m  0.25 mm; column temp., 1058): tR((1R,5S)-12c (major)) 17.6 min; tR
((1S,5R)-12c (minor)) 17.9 min; tR ((1S,5R)-13c (major)) 16.6 min; tR ((1R,5S)-13c (minor)) 16.8 min. Optical
activity of the 12c/13c 7:3: [a]Dr:t: ˆ ‡65.2 (c ˆ 1.00, MeOH) ([73]: (1S,5R)-12c: [a]rD:t:
ˆ
104 (c ˆ 1.2, MeOH);
[34][74]: (1R,5S)-13c: [a]Dr:t:
ˆ
67.9 (> 95% ee; c ˆ 2.3, CHCl3)); with the same assumption made for the 12b/
13b mixture above, we calculated ‡ 838 for the optical activity of the mixture of 67% (1R,5S)-12c, ‡ 5%
(1S,5R)-12c, ‡ 28% (1S,5R)-13c, ‡< 1% (1R,5S)-13c (cf. Entry 4 in the Table). The NMR spectra of 12c and
13c were interpreted by comparison with the spectrum of rac-12c (96%)/rac-13c (4%), as obtained from rac-11c
1
and H2O2/HOAc (see Sect. 9). H-NMR (300 MHz): 12c: 2.40 ± 2.82 (m, 4 H); 3.48 ± 3.56 (m, 1 H); 5.11 ± 5.16
(m, OCH); 5.57 ± 5.61 (m, CˆCH); 5.78 ± 5.82 (m, CˆCH); 13c: 2.70 ± 2.79 (m, 2 H); 3.11 ± 3.17 (m, 1 H);
3.50 ± 3.66 (m, 1 H); 4.25 (dd, J ˆ 1.6, 9.3, OCH); 4.43 (dd, J ˆ 7.0, 9.3, OCH); 4.65 ± 5.69 (CˆCH); 5.85 ± 5.89
(CˆCH). 13C-NMR (100 MHz): 12c: 33.01; 39.27; 45.34; 82.91 (CO); 129.61 (CˆC); 131.26 (CˆC); 176.79
(CˆO); 13c: 36.28; 41.44; 46.21; 71.35 (CO); 130.61 (CˆC); 132.30 (CˆC); 180.96 (CˆO). The NMR data
were in accordance with the literature values reported for 12c [72] and 13c [74].
8.4. Kinetic Resolution of exo-Tricyclo[4.2.1.02,5]nonan-3-one: (‡)-exo-Tricyclo[4.2.1.02,5]nonan-3-one
(11d), 3-Oxatricyclo[5.2.1.02,6]decan-4-one (12d), and 4-Oxatricyclo[5.2.1.02,6]decan-3-one (13d). rac-exo-
Tricyclo[4.2.1.02,5]nonan-3-one (136.2 mg, 1.0 mmol) was allowed to react with 3 in the presence of DBU and
LiCl, according to GP 3. The crude product was purified by FC (15 g of SiO2; hexane/Et2O 10 :1 ! 5 :1 ! 1:2)
to yield 11d (30.6 mg, 0.225 mmol, 22.5%) as a colorless oil and a 6 :4 mixture 12d/13d (not separable by FC;
108.1 mg, 0.710 mmol, 71.0%) as a colorless oil of [a]rD:t: ˆ ‡25.5 (c ˆ 1.00, CHCl3).
Data of 11d: 59% ep (GC analysis). GC (column: Alpha Dex 120, 30 m  0.25 mm; column temp., 1008): tR
((‡)-11d (major)) 12.8 min; tR (( )-10d (minor)) 13.1 min. [a]rD:t: ˆ ‡43.1 (c ˆ 1.00, CHCl3). 1H-NMR

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Helvetica Chimica Acta ± Vol. 84 (2001)
(300 MHz): 1.07 ± 1.27 (m, 3 H); 1.44 ± 1.67 (m, 3 H); 2.23 ± 2.30 (m, 1 H); 2.39 ± 2.43 (m, 2 H); 2.49 ± 2.57
(m, 1 H); 2.98 ± 3.02 (m, 1 H); 3.07 ± 3.10 (m, 1 H). 13C-NMR (100 MHz): 26.57; 28.18; 31.10; 32.23; 37.14;
39.44; 50.21; 68.02; 212.94 (CˆO). The NMR data were in accordance with the literature values [57].
Data of 12d/13d: 12d: 88% ep; 13d: 99% ep (GC analysis). GC (column: Beta Dex 120, 30 m  0.25 mm;
initial column temp., 858 (11 min); heating rate, 108/min (to 1508)); tR (12d (major)) 30.9 min; tR (12d (minor))
31.3 min; tR (13d (major)) 29.5 min; tR (13d (minor)) 29.7 min. The abs. configurations shown in the formulae for
11d, 12d, and 13d in Sect. 5 of the general part have been drawn by analogy with the series of bicyclic compounds
11a, 12a/11b, 12b, 13b/11c, 12c, 13c, without any experimental evidence! The NMR spectrum of the 6 :4 12d/13d
mixture could be interpreted, and the signals assigned by comparison with published spectra of 12d [75] and 13d
[76]. 1H-NMR (300 MHz): 12d: 1.08 ± 1.78 (m, 6 H); 2.08 ± 2.78 (m, 5 H); 4.46 ± 4.49 (m, OCH); 13d: 1.08 ± 1.78
(m, 6 H); 2.08 ± 2.78 (m, 4 H); 3.90 (dd, J ˆ 3.7, 9.6, OCH); 4.42 (d, J ˆ 9.6, OCH). 13C-NMR (100 MHz): 12d:
23.17; 27.88; 31.28; 33.29; 40.86; 41.84; 47.99; 86.40 (CO); 178.11 (CˆO); 13d: 27.14; 27.78; 33.38; 40.47; 41.63;
41.70; 42.59; 72.81 (CO); 179.49 (CˆO).
9. Determination of the Absolute Configuration of 11b, 11c, 12b, 12c, 13b, 13c. Compound (‡)-11c (90% ep,
90.0 mg, 0.83 mmol; from the kinetic resolution of rac-11c) was oxidized with 30% H2O2 in AcOH according to
the procedure in [77]. The crude product was purified by FC (10 g of SiO2; pentane/Et2O 4 :1) to yield a 96 :4
mixture of normal lactone 12c and abnormal lactone 13c (50.0 mg, 0.403 mmol, 48.6%) as a colorless oil. 12c:
90% ep; 13c: 90% ep (GC analysis). GC (column: Alpha Dex 120, 30 m  0.25 mm; column temp., 1058: tR (12c
(minor)) 17.6 min; tR (12c (major)) 17.9 min; tR (13c (major)) 16.6 min; tR (13c (minor)) 16.8 min. Optical
activity of the 96 :4 mixture 12c/13c [a]Dr:t:
and comparison of the tR values of 12c and 13c from the kinetic resolution and from the oxidation of (‡)-
(1R,5S)-11c (see Scheme 7) led to the assignments as given in the procedure, above, in the Table, and in
Scheme 6.
ˆ
83.6 (c ˆ 1.00, MeOH). Optical comparison with literature values
Scheme 7. The Absolute Configuration of 11c, 12c, and 13c by Independent Formation of 12c and 13c from the
Product 11c of Kinetic Resolution
(90% (1R,5S) ‡ 10% (1S,5R))(90% (1S,5R) ‡ 10% (1R,5S))(90% (1S,5R) ‡ 10% (1R,5S))
([73]: (1S,5R)-12c [a]Dr:t:
([74]: (1R,5S)-13c [a]Dr:t:
ˆ
ˆ
104)
67.9)
Compound (‡)-(1R,5S)-11c (90% ep; as obtained from a kinetic resolution experiment; see Entry 4 in the
Table) was hydrogenated (H2, atmospheric pressure, 10% Pd/C, AcOEt) to give (S,S)-11b, 90% es (GC
analysis). GC (column: Beta Dex 120, 30 m  0.25 mm; column temp, 858: tR ((R,R)-11b (minor)) 10.3 min; tR
((S,S)-11b (major)) 10.6 min. Thus, the unsaturated (11c) and the saturated (11b) bicyclo[3.2.0]heptanone, as
recovered from the kinetic resolutions, are correlated by chemical conversion (11c ! 11b) and by comparison of
the tR values of the major and the minor enantiomers on a chiral column.
The 96 :4 mixture (1S,5R)-12c/(1S,5R)-13c, both of 90% ep (see above, and Scheme 7), was hydrogenated
(H2, atmospheric pressure, 10% Pd/C, AcOEt) to give a 96 :4 mixture (S,S)-12b/(1S,5R)-13b, both of 90% ep
(GC analysis). GC (column: Alpha Dex 120, 30 m  0.25 mm; column temp, 958): tR ((R,R)-12b (minor))
30.7 min; tR ((S,S)-12b (major)) 31.0 min; tR ((1S,5R)-11b (major)) 28.6 min; tR ((1R,5S)-13b (minor)) 29.0 min.
With the known absolute configurations of the enantiomers of 12c and of 13c (see above and Scheme 7) and by
comparison of the tR values of major and minor enantiomer components from the products of kinetic resolution
and of H2O2 oxidation of (1R,5S)-11c, we can thus assign the absolute configurations of 12b and 13b as given in
the procedures above, in the Table, and in Scheme 6.
10. X-Ray Crystal-Structure Determination of TADOOH 3 ´ DMF Complex (see Fig. 1). From a crystal of
size 0.30 Â 0.10 Â 0.10 mm, 1605 reflections were measured on an Enraf Nonius CAD-4 Diffractometer with
CuKa radiation (graphite monochromator, l ˆ 1.54184 Š). For determination of the absolute configuration, the

Helvetica Chimica Acta ± Vol. 84 (2001)
205
Friedel pair of every reflection was measured as well. The structure was solved by direct methods with SIR97
[78]. The non-H-atoms were refined anisotropically with SHELXL-97 [79]. The H-atoms were calculated at
idealized positions and included in the structure factor calculation with fixed isotopic displacement parameters.
C34H37NO6, Mol.-wt. 555.65, crystallized from DMF/Et2O/hexane, temp. 293(2) K, orthorhombic, space group
P212121, a ˆ 9.790(10) Š, b ˆ 11.781(13) Š, c ˆ 26.00(3) Š, a ˆ 908, b ˆ 908, g ˆ 908, Vˆ 2999(6) Š3, Z ˆ 4,
1calc. ˆ 1.231 g ´ cm 3, m ˆ 0.677 mm 1, F(000) ˆ 1184. Number of reflections collected 1605 (w scan, 3.40 < q <
47.46), 1605 independent reflections, 1605 reflections observed, criterion I > 2s(I), final R ˆ 3.45%, wR2 ˆ
3
8.84%, goodness of fit 1.097, D1 (max, min) 0.131 eŠ
,
0.125 eŠ 3. Crystallographic data (excluding structure
factors) for the structure of 3 have been deposited with the Cambridge Crystallographic Data Centre as
deposition No. CCDC-148646. Copies of the data can be obtained, free of charge, on application to the CCDC,
12 Union Road, Cambridge CB21EZ UK (fax: ‡ 44(1233)336033; e-mail: deposit@ccdc.cam.ac.uk).
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