Mechanism of the asymmetric sulfoxidation in the esomeprazole process: Effects of the imidazole backbone for the enantioselection

Article abstract of DOI:10.1002/adsc.200800753

The asymmetric sulfoxidation reaction of imidazole-based prochiral sulfides was studied to explore the mechanistic details of the highly efficient esomeprazole process, which is one of the few industrial scale catalytic asymmetric procedures. The syntheti

Full text of DOI:10.1002/adsc.200800753

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DOI: 10.1002/adsc.200800753
Mechanism of the Asymmetric Sulfoxidation in the
Esomeprazole Process: Effects of the Imidazole Backbone
for the Enantioselection
Muthu Seenivasaperumal,a Hans-Jꢀrgen Federsel,b and Kꢁlmꢁn J. Szabꢂa,*
a
Stockholm University, Arrhenius Laboratory, Department of Organic Chemistry,
SE 106 91 Stockholm, Sweden
Fax : (+46)-8-154908; e-mail: kalman@organ.su.se
Global Process R&D, AstraZeneca, SE 151 85 Sçdertꢃlje, Sweden
b
Received: December 3, 2008; Revised: March 23, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800753.
Abstract: The asymmetric sulfoxidation reaction of ciate the coordinated imidazole substrate. The densi-
imidazole-based prochiral sulfides was studied to ex- ty functional theory (DFT) modelling studies provid-
plore the mechanistic details of the highly efficient ed new insights in the mechanism of the asymmetric
esomeprazole process, which is one of the few indus- induction. It was found that the oxidation requires a
trial scale catalytic asymmetric procedures. The syn- lower activation energy if the imidazole sulfide pre-
thetic studies revealed that the smallest subunit gov- cursor does not coordinate to titanium. Two possible
erning the selectivity in the esomeprazole process is reaction paths were explored for this out of sphere
an imidazole ring. Thus, by using the esomeprazole oxidation mechanism. The most important interac-
procedure methyl imidazole sulfide could be oxi- tion governing the enantioselection is hydrogen
ꢀ
dized as efficiently as its several functionalized deriv- bonding between the N H of the imidazole ring and
atives, including pyrmetazol. However, alkylation of the chiral tartrate ligand on titanium. Furthermore,
the imidazole nitrogen led to a major drop of the the oxidation reaction imposes an important structur-
enantioselectivity. Our atmospheric pressure chemi- al constraint to the TS structure involving a linear ar-
cal ionization-mass spectrometry (APCI/MS) studies rangement of the peroxide oxygens and the sulfur
indicate that addition of small amounts of water to atom. This constraint and the N coordination of imi-
the reaction mixture facilitates the formation of dazole leads to a very strained structure for the inner
mononuclear titanium species, which are the active sphere mechanism of the oxidation, which leads to a
catalytic intermediates of the selective oxidation re- much higher activation barrier than the correspond-
action. One of the most important features of the ing out of sphere process, and therefore it is unlikely.
esomeprazole procedure is that amine additives in-
crease the enantioselectivity of the oxidation process.
The NMR studies of the presumed reaction inter- Keywords: asymmetric catalysis; density functional
mediates show that under catalytic conditions the theory; nitrogen heterocycles; oxidation; sulfoxides;
amines are able to coordinate to titanium and disso- titanium
Introduction
process has become an important source of inspira-
tion and reference point for academic research to de-
Esomeprazole, the active ingredient of Nexium, is velop new efficient asymmetric catalytic methods rel-
produced on a multi-ton scale per annum by using an evant for the pharmaceutical industry and for the syn-
efficient titanium tartarate-based asymmetric sulfoxi- thesis of specialized chemicals. Optically active sulfox-
dation process.[1–3] This process is one of the few ides,[5–10] in general, represent an important class of
large-scale asymmetric catalytic applications that sat- pharmaceuticals and drug intermediates.[11] They
isfies the rigorous selection criteria of atom economy often play an important role as therapeutic agents,
and ecoefficiency required for modern industrial man- such as anti-ulcer (proton pump inhibitors),[12–16] anti-
ufacturing processes.[4] Accordingly, the esomeprazole bacterial, anti-atherosclerotic,[17–19] anthelmintic,[20]
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Muthu Seenivasaperumal et al.
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tionally simple and highly efficient esomeprazole pro-
cedure.
Results and Discussion
Structural Requirements of the High Selectivity in the
Esomeprazole Process
The main objective of our initial studies was to identi-
fy the most important structural motif in pyrmetazole
(1h) required for the high level of enatioselection to
obtain esomeprazole (2h). In these studies we em-
ployed a laboratory scaled version of the esomepra-
zole procedure.[1,2]
Figure 1. Asymmetric sulfoxidation of imidazole derivatives
using the the esomeprazole process.
Accordingly, in a typical procedure the correspond-
ing prochiral sulfide 1a–i (1.0 equiv.), a catalytic
and cardiotonic agents[21] as well as psychotonics[22] amount of diethyl tartrate 4 (0.6 equiv.) and water
and vasodilators.[23] Thus, several methods have been (0.2 equiv.) were conditioned at 508C for 15 min.
developed for the asymmetric oxidation of prochiral Then, titanium catalyst 3 (0.3 equiv.) was added and
sulfides with chiral metal complex catalysts, such as ti- the conditioning procedure was continued at the same
tanium-,[2,24–36]
manganese-,[37–39]
vanadium-,[40–46] temperature for additional 45 min. Subsequently,
iron-,[47–49] and aluminium-based[50] systems.
Hꢀnigꢅs base 5a (0.3 equiv.) and cumene hydroperox-
Despite the above-mentioned practical importance ide 6 (1.0 equiv.) were added and the reaction mixture
of the asymmetric sulfoxidation reactions, the basic obtained was stirred at the temperatures and times
mechanistic features of the titanium tartrate-based given in Table 1. By strict application of this protocol
process used for the synthesis of esomeprazole over-oxidation of the sulfoxide products to sulfones
(Figure 1) remained mainly unexplored. In particular, could be avoided. However, application of an excess
effects of the applied water, function of the catalytic of 6 and/or application of higher temperatures or
amounts of amine (5a) and the mechanism of the longer reaction times than given in Table 1 led to for-
asymmetric induction have been the subject of great mation of varying amounts of sulfone products.
interest and curiosity. Therefore, we have initiated a
research program to rationalize the surprisingly high
Under the employed conditions (Table 1), methyl-
AHCTUNGTREGiNNUN midazole 1a (entry 1) and benzimidazole 1e (entry 6)
level of enantioselection achieved for heterocyclic were oxidized with the same enantioselectivity (96–
sulfoxides using this simple yet very efficient catalytic 97% ee) as pyrmetazole 1h in both the laboratory
system. Previously, we have communicated[51] our re- scale (entry 9) and in the industrial scale[1] process.
sults (Figure 1, Table 1) on the selectivity of asymmet- Substitution of the carbon atoms of the imidazole
ric oxidation of prochiral sulfides 1a–i with heterocy- (1b) or benzimidazole (1g) rings had minor effects on
clic backbones. These studies have shown that the the enantioselectivity of the reaction (entries 5 and 8).
asymmetric induction in the esomeprazole process Likewise, replacement of the methyl substituent with
can be attributed to a relatively small and well de- a benzyl substituent (1c) had an insignificantly small
fined structural motif of the substrate (1h). In this effect on the level of the enantioselection (entry 4).
paper we give a full account of our results significant- This remarkable maintenance of the selectivity is ap-
ly extending the discussion of the mechanistic features parently due to the effects of the imidazole ring of 1c,
of the catalytic reactions. The new features involve since the corresponding phenyl derivative 1i is oxi-
the following aspects: i) studies on the effects of dized with a low enantiomeric excess (entry 10) under
water using APCI-mass spectrometry; (ii) isolation of the same reaction conditions. Literature examples[36,46]
possible catalytic intermediates; (iii) rationalization of show that the enantioselectivity of the oxidation of 1i
the effects of added amines, such as 5a; and (iv) to 2i can be improved by replacement of 4 by other li-
based on the experimental studies DFT modelling of gands or by using a vanadium-based catalyst. Our
the possible catalytically important species and the studies have also shown that a major drop of the
asymmetric induction of the sulfoxidation.
enantioselectivity takes place when one of the nitro-
A particularly important aspect of this study is the gen atoms of the imidazole ring is methylated. Thus,
assessment of the steric and electronic factors enhanc- oxidation of N-methyl derivatives 1b and 1f gave rac-
ing the enantioselectivity of the oxidation of prochiral emic sulfoxides (entries 3 and 7).
heterocyclic compounds, to inspire new laboratory
These studies have shown that the smallest
and industrial scale applications based on the opera- common structural motif required for the selective
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Mechanism of the Asymmetric Sulfoxidation in the Esomeprazole Process
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Table 1. Dependence of the enantiomeric excess on the structure of the aromatic motif in asym-
metric oxidation of prochiral sulfides.
[a]
The reactions were conducted in toluene according to the reaction conditions given in
Figure 1.
Temperature/reaction time [8C/h].
Isolated yield.
Enantiomeric excess.
[b]
[c]
[d]
[e]
Chloroform was used as solvent.
sulfoxidation of 1a–h is an imidazole ring with unsub- plore the imidazole effects in the esomeprazole pro-
stituted ring nitrogens. The high enantioselectivity is cess.
nicely maintained when the other substituent on the
sulfur atom is a relatively bulky group such as in 1c
and 1h. Considering these, we directed our further Effects of the Added Water on the Outcome of the
studies to the rationalization of the favourable fea- Catalytic Process
tures of the imidazole ring on the enantioselection in
the titanium-catalyzed sulfoxidation reaction. Since 1a Addition of water to the titanium tartrate catalytic
and product 2a are much easier to handle and much system is very important to achieve high levels of
less bulky than pyrmetazole 1h and esomeprazole 2h, enantioselection in the sulfoxidation reaction.[1,2,5,8,24]
we employed these species as model compounds in Kagan and co-workers pointed out that application of
our further experimental and modelling studies to ex- two equivalents of diethyl tartrate (4) relative to the
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Figure 2. APCI mass spectrum of sample (i) prepared from 3 and 4 (1:2 ratio) in the absence of added water.
titanium catalyst 3 and application of water leads to a the proper solvent is very important in this method to
change of the structure of the Sharpless reagent[52–54] obtain mild but efficient ionization of the analyte. Un-
generated when the 4 to 3 ratio is restricted to 1:1. fortunately, toluene employed in the original proce-
The Sharpless reagent has a well-established binuclear dure did not prove to be useful because of the ineffi-
structure,[53,54] however, it is not per se efficient for the cient ionization of the intermediate titanium com-
asymmetric sulfoxidation of prochiral sulfides.[24] Con- plexes. This problem could be solved by replacement
sequently, the ratio of 3 to 4 and the amount of added of toluene with chloroform, which proved to be a sat-
water induce structural changes, which are specifically isfactory medium for both the APCI analysis and for
important for the asymmetric induction of the sulfoxi- the enantioselective sulfoxidation reaction (Table 1,
dation reaction. In this respect the mechanistic picture entry 2).
given by Bolm and co-workers[8] is particularly impor-
In order to explore the effects of the added water
tant. These authors assumed that the active species in to the equilibration step of the sulfoxidation reaction,
the catalytic version of the sulfoxidation reaction (ap- we have prepared two samples. The first sample (i)
plying a 1:2 ratio for 3/4 and water as additive) is a was prepared by dissolving diethyl tartrate
4
monomeric titanium complex. (2 equiv.) in 0.5 mL of chloroform at 508C for 15 min
Mild ionization techniques[55,56] based on atmos- followed by addition of titanium isopropoxide (3)
pheric pressure chemical ionization (APCI) and elec- (1 equiv.). This mixture was stirred at 508C for further
trospray ionization (ESI) have become useful tools 45 min. The second sample (ii) was prepared in the
for analysis of the reaction intermediates.[57–59] Appli- same way, except that 1 mL water was also added.
cation of a mild ionization technique[55,57] has also Prior to the APCI analysis, the samples were cooled
been indispensable in analysis of the intermediate down and diluted with 5 mL of chloroform. The dilu-
complexes generated from 3, 4 and water in the reac- tion was required to obtain an optimal analyte con-
tion conditions of the catalytic asymmetric oxidation centration. The APCI analysis of sample (i) without
of 1. After extensive studies we have found that the added water showed two important peaks at m/z=
APCI method (in negative ion mode) is more robust 491.0 (7) and 947.16 (8) in a 4:1 ratio (Figure 2). We
and efficient[57] for the detection of the reaction inter- have found that addition of water induced significant
mediates, than the ESI method, and therefore this changes in the spectrum. Thus, the APCI spectrum of
method was applied for the analysis of the reaction sample (ii) showed that the ratio of the two species 7
mixtures. In order to study the effects of added water, and 8 was changed to 17:1.
we have attempted to apply the reaction conditions of
Simulation of the isotope pattern (given in the sup-
the equilibration step (see above) adapted to the ioni- porting information) of the species at m/z=491.1 in-
zation conditions of the APCI method. The choice of dicated that this species (7) contains a single titanium
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Mechanism of the Asymmetric Sulfoxidation in the Esomeprazole Process
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Figure 3. APCI mass spectrum of sample (ii) prepared from 3 and 4 (1:2 ratio) in the presence of added water.
atom, while the isotope pattern for the peak at m/z= studies to establish the role of the substrate (1) and
947.1 (8) is characteristic for a binuclear titanium the applied amine (5) using APCI did not give unam-
complex. The MS/MS studies have shown that 7 and 8 biguous results, therefore we continued our studies
are inter-related, as fragmentation of binuclear spe- with other techniques.
cies 8 gave predominantly mononuclear species 7.
Considering the observed molecular weight of the
complexes, our assumption is that 7 is a titanium di- Role of the Amine Additive in the Sulfoxidation
tartrate complex, while 8 is a binuclear titanium com- Process
plex incorporating four diethyl tartrate molecules
(Figure 2 and Figure 3). The suggested hydroxy li- Catalytic Studies
gands may arise from water, which is certainly present
in trace amounts even in sample (i) prepared without One of the most important differences between
intentionally adding water.
Kaganꢅs[24] Orsay procedure and the esomeprazole
Accordingly, addition of water increases the con- process[1,2] is application of an amine base (such as 5a)
centration of mononuclear species 7 at the expense of as a crucial component in the latter case. It was re-
binuclear species 8 in the reaction mixture of the sul- ported that the enantioselectivity of the oxidation of
foxidation. Furthermore, other intensive peaks (at pyrmetazole (1h) to esomeprazole (2h) is lowered in
m/z=833.1 and 759.1, Figure 2) generated by com- the absence of Hꢀnigꢅs base (5a). Indeed, the selectiv-
plexes with typically dinuclear isotope patterns are ity of oxidation of 1a to 1b in the absence of 5a shows
also suppressed or completely disappear in the pres- a similar tendency (Figure 4). Thus, the enantioselec-
ence of added water (Figure 3). These findings strong- tivity dropped from 97% (Table 1, entry 1) to 77%,
ly suggest that the main role of the added water and when Hꢀnigꢅs base was not applied as additive.
also the use of excess of 4 is to generate a high con-
It was shown that the esomeprazole process still
centration of monomeric titanium species, which are works selectively by replacing 5a with other amines.[2]
the active species of the catalytic process.[8] Further Likewise, we have found that replacement of 5a
Figure 4. In the absense of 5a the enantioselectivity of the sulfoxidation is decreased.
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Table 2. Dependence of the selectivity on variation of the employed base.[a]
[a]
[b]
The reactions were conducted at ꢀ208C for 1.5 h in toluene according to the reaction
conditions given in Figure 1.
Isolated yield.
(Table 2, entry 1) with imidazole (5b) or aniline deriv- Table 3. Selectivity in asymmetric oxidation of 1a in the ab-
sence of 5a.[a]
atives 5c–e affects only sligthly the enantioselectivity.
It is interesting to point out that imidazole 5b
(entry 2), which is the structural analogue of substrate
1a, gives the same high selectivity as 5a.
Time [min][b]
ee [%][c]
Conversion of 1a [%][d]
15
45
60
90
94
89
81
77
60
70
82
100
These findings show that the addition of amine ad-
ditive increases the selectivity of the sulfoxidation,
however Hꢀnigꢅs base can be replaced by several
other species. In fact, substrate 1a also incorporates a
nitrogen atom, which may exert the same effects, as
the corresponding functionality in 5a. Considering the
fact that imidazole (5b) could fully replace 5a in the
selective sulfoxidation reaction, it is reasonable to
assume that S-methylimidazole 1a is also able to act
as nitrogen base in the process until it is consumed.
Indeed, we found that after 15 min of reaction time,
[a]
The reactions were conducted under standard condition
in the absence of 5a (Figure 6).
Elapsed reaction time.
Enantiomeric excess.
Conversion of 1a determined by H NMR.
[b]
[c]
[d]
1
when about 40% of substrate 1a was still present in tion that even without additives (such as 5a) the enan-
the reaction mixture (Table 3), the selectivity of the tioselectivity of the sulfoxidation of 1a is high at low
oxidation (94% ee) was about the same as in the pres- conversions (Table 3), as 1a itself is available to coor-
ence of 5a (97% ee, Table 1, entry 1). However, as 1a dinate to titanium, and thus enhance the enantioselec-
was consumed, the ee was successively decreased to tivity
77% until the conversion of 1a was completed. Con-
sidering the fact that various nitrogen-containing spe-
cies 5b-e (Table 2) with different basicity are able to Stoichiometric Studies to Detect Reaction
maintain the high selectivity of the sulfoxidation pro- Intermediates
cess, the main effect of 5a in the enantioselection pro-
cess is probably not exerted by a simple deprotona- The APCI/MS studies (see above) indicated that the
tion of substrate 1a but possibly via coordination to ti- conditioning process of the sulfoxidation reaction (see
tanium. This would also explain the above observa- above) is very important to generate the active cata-
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lytic intermediates of the reaction. Therefore, we ed by the small but significant changes of the NMR
have attempted to observe additional catalytic inter- shift values between its complexed and free forms
mediates of the conditioning step. In these studies we (Table 4). Compound 1a may coordinate via either its
mixed 1a, 4 and water (1.0/0.3/0.15 equiv.) and heated nitrogen or its sulfur atom to titanium. The N-coordi-
them to 508C for 15 min in chloroform followed by nation to titanium is suggested by the fact that the de-
addition of 3 (0.15 equiv.), and heating at 508C for viation of the 13C NMR shifts of 1a is strongest for
45 min. After this conditioning procedure, the reac- the double bonded carbons C4 and C5 (2.07 ppm),
tion mixture was cooled and ether was added, which and still large for C2 (1.63 ppm), while it is relatively
led to precipition of a white solid. Unfortunately, we small for SCH3 (0.94 ppm).
were not able to obtain crystals from this white solid,
Subsequently, we have studied the behaviour of
and therefore it was studied by NMR spectroscopy. complex 9 on addition of Hꢀnigꢅs base 5a. As men-
The obtained substance was almost completely insolu- tioned above, complex 9 was practically insoluble in
ble in chloroform, and therefore the NMR studies chlorform. However, when 5a was added to a suspen-
were carried out in MeOH-d4. These studies have sion of complex 9 the white solid was immediately
shown that the complex contained 1a and diethyl tar- dissolved indicating that amine 5a is coordinated to
trate 4 in a 1:1 stoichiometry. Considering the fact the complex, which became readily soluble in chloro-
that the APCI studies indicated that the dominating form. Coordination of 5a to titanium could be con-
species are mononuclear in the presence of water, we firmed by systematic changes of its NMR shifts
identified the white solid obtained in the conditioning (Figure 6, Table 5). In particular, the shift value of C1
process as
a
mononuclear titanium complex
9
and C2 changed (by 3.38 and 2.29 ppm) in 5a after ad-
(Figure 5, Table 4). Complexation of 1a is also indicat- dition to complex 9 (Figure 6). On the other hand the
shift values of substrate 1a in this reaction mixture
and in free form agreed within 0.5 ppm (Figure 6),
and therefore we conclude that coordination of 5a
leads to dissociation of 1a from complex 9. Overall,
addition of Hꢀnigꢅs base 5a to complex 9 obtained
from the reaction mixture of the conditioning process
triggers a ligand exchange process, in which 5a repla-
ces 1a.
We have also employed complex 9 as catalyst in the
asymmetric oxidation of 1a (Figure 7). These studies
have shown that complex 9 is an active catalyst in the
sulfoxidation. In the presence of 5a product 2a was af-
forded with a relatively good selectivity. When the re-
Figure 5. Tentative structure of the complex isolated from
the reaction mixture of the conditioning process.
Table 4. Comparison of the NMR shift values of sulfide 1a
in 9 and in uncomplexed form.[a]
Table 5. Comparision of the 13C NMR shift values of 5a in
complex 10 and in its free form.[a]
Nucleus
Complex 9
Free 1a
D [ppm][b]
H4, H5
SCH3
C4, C5
C2
7.34
2.68
122.07
142.25
16.96
7.04
2.51
120.00
140.62
16.02
0.30
0.17
2.07
1.63
0.94
Carbon
Complex 10
Free 5a
D [ppm][b]
C1
C2
C3
51.79
41.28
19.75
48.41
38.99
20.58
3.38
2.29
ꢀ0.83
SCH3
[a]
[a]
1H NMR (ppm) and 13C NMR (ppm) shift values record-
ed in MeOH-d4.
Difference between the shift values of the complexed
and free 1a.
Shift values recorded in CDCl3. Numbering of 5a is given
in Figure 6.
[b]
[b]
Differences between the shift values of the complexed
and free 5a.
Figure 6. Addition of Hꢀnigꢅs base to 9 leads to formation of 10 by ligand exchange.
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which was modelled by strongly simplified species, as,
at the date of this study (1994) inclusion of the tar-
trate ligand, was not realistic. The possible mechanism
of the enantioselection was studied by molecular me-
chanics calculations. In these studies Jørgensen[60] also
gave a useful MO interpretation for the transition
state of the oxidation step, which nicely rationalizes
the geometrical constraints imposed by the transfer of
the oxygen atom from the titanium coordinated per-
oxide molecule to the sulfur atom of the pro-chiral
sulfide.
Our main intention was, of course, the modelling of
the enantioselection of the esomeprazole process by
DFT calculations. As we have shown (see above)
methylimidazole 1a is oxidized as efficiently and se-
Figure 7. Application of complex 9 as catalyst in the sulfoxi-
dation reaction in the presence and absence of 5a.
action was carried out without amine 5a the enantio- lectively as pyrmetazole, we thus chose this species as
selectivity was significantly lowered, similar to the the prochiral sulphide for the modelling studies. In
original process carried out according to the esome- fact, from the very beginning of the project we have
prazole procedure[1,2] (Figure 4). The fact that com- intended to find the smallest possible prochiral sulfide
plex 9 in the presence of 5a shows a high catalytic aci- substrate to decrease the computational burden of the
tivity and relatively good enantioselectivity indicates modelling studies.
that 9 and 10 and/or closely related analogues are the
true reaction intermediates of the sulfoxidation reac-
tion of 1a in the esomeprazole procedure.
Computational Methods
The results presented in this section indicate that
5a and other amines (Table 2) are important additives All geometries were fully optimized employing a
in the esomprazole procedure to increase the enantio- Becke-type[61] three-parameter density functional
selectivity of the process. In the first conditionation model B3LYP[62,63] using a 6-31G* basis set.[64,65] Har-
step, a titanium-diethyl tartrate (DET) substrate com- monic frequencies have been calculated at the level
plex (such as 9) is formed, which then undegoes of optimization for all structures to characterize the
ligand exchange with the amine additive to give a calculated stationary points and to determine the
new titanium-DET amine complex (such as 10). Ac- zero-point energies and other thermodynamical
cordingly, 5a (or other amines) serves as a ligand on energy contributions. Fully optimized transition state
titanium, and its ligand effects are important to in- structures
crease the enantioselectivity of the sulfoxidation pro- Figure 13) have been characterized by a single imagi-
cess. nary frequency, while the rest of the optimized struc-
11–13R/S-TS
(Figure 11,
Figure 12,
The results of this and the previous sections give tures possess only real frequencies. All calculations
important suggestions about the active intermediates were carried out by employing the Gaussian 03 pro-
and give several hints for a rationalization of the gram package.[66]
mechanism leading to the enatioselection. Based on
these results, the steric and electronic effects of the
tartrate and the amine ligands (4 and 5, respectively) Modelling Strategies
on the enantioselection process were studied by DFT
modelling studies.
The relatively small prochiral substrate allowed us to
perform a DFT modelling study with only minor trun-
cation of the realistic reaction components. The sim-
plifications involved the following: (i) in the model-
ling studies we employed dimethyl tartrate, instead of
diethyl tartrate; (ii) Hꢀnigꢅs base 5a was replaced by
DFT Modelling Studies of the Mechanism of the
Enantioselection
In spite of the large importance of titanium-catalyzed trimethylamine; (iii) cumene peroxide was modelled
asymmetric sulfoxidation reactions, there are surpris- by methyl peroxide; and (iv) the isopropoxide ligand
ingly few theoretical studies published on the mecha- was replaced by a methoxide ligand. Considering our
nism of the oxidation and the possible ways of the findings on the effect of water (see above) and previ-
chiral induction. Jørgensen[60] has published a study ously published mechanistic suggestions,[8,60] we per-
on the mechanism of the sulfoxidation modelling the formed the DFT calculations for mononuclear com-
Orsay conditions.[24] This work involved a quantum plexes. The peroxide molecule was assumed to coordi-
chemical (Hartree–Fock) study of the core reaction, nate in an h2-fashion to the titanium atom in line with
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Mechanism of the Asymmetric Sulfoxidation in the Esomeprazole Process
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previous studies and mechanistic suggestions,[8,60,67]
Although, Kagan has pointed out that the sulfide sub-
.
The Out of Sphere Mechanism of the Sulfoxidation
strate is probably not coordinated to titanium under We have localized (Figure 8 and Figure 9) two dis-
the sulfoxidation reaction (and our studies[51] have tinctly different Ti-tartrate-peroxide complexes with a
confirmed this suggestion), we studied two distinct ox- coordinated Me3N molecule (11 and 12). In these
idation pathways: (i) without coordination of imida- complexes 1a is not able to directly coordinate to tita-
zole sulfide (1a) to titanium (Figure 8 and Figure 9). nium (Figure 11 and Figure 12). However, 1a is bound
In this case trimethylamine is coordinated to titanium to the tartrate ligand by a firm hydrogen bonding.
ꢀ
(see above); and (ii) when 1a is coordinated to titani- This hydrogen bond involves the N H proton of the
um and undergoes an inner-sphere oxidation process imidazole ring and the alkoxide (11, Figure 11) or the
(Figure 10).
carbonyl group (12, Figure 12) of the tartrate ligand.
This hydrogen bonding is very important in position-
Figure 8. Reaction path Ia for out of sphere oxidation of methyl imidazole sulfide 1a. The Gibbs free energy values and the
total energy differences (in parentheses) are given in kcalmolꢀ1.
Figure 9. Reaction path Ib for out of sphere oxidation of methyl imidazole sulfide 1a. The Gibbs free energy values and the
total energy differences (in parentheses) are given in kcalmolꢀ1.
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Figure 10. Reaction path II for inner sphere oxidation of methyl imidazole sulfide 1a. The Gibbs free energy values and the
total energy differences (in parentheses) are given in kcalmolꢀ1.
Figure 11. Selected calculated structures for path Ia (cf. Figure 8). The distances are given in ꢆ units and the Gibbs free
energy values and the total energy differences (in parentheses) are given in kcalmolꢀ1.
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Mechanism of the Asymmetric Sulfoxidation in the Esomeprazole Process
FULL PAPERS
Figure 12. Selected calculated structures for path Ib (cf. Figure 9). The distances are given in ꢆ units and the Gibbs free
energy values and the total energy differences (in parentheses) are given in kcalmolꢀ1.
ing of the pro-chiral sulfide (1a) with respect to the quires a lower activation barrier by 4 kcalmolꢀ1 than
chiral titanium complex, and it is also preserved the R form (11R-TS). Since formation of the S-prod-
under the entire oxidation process.
uct (11S-prod) of path Ia represents the lowest energy
Path Ia: ꢀC1 omplex 11 is more stable than 12 by reaction path compared to other possible reaction
ꢀ
5.4 kcalmol . In this complex (11) the N H proton channels (path Ib and path II), our theoretical model
of the imidazole molecule is coordinated to the front predicts predominant formation of methylimidazole
side alkoxide atom of the tartrate ligand (Figure 11). sulfoxide with S-configuration (2a), which is in agree-
The rear side of the tartrate molecule is effectively ment with the experimental findings (Table 1).
blocked by the Me3N ligand. Two TS structures were
One of the most important structural features of
localized for the oxidation reaction starting from com- the TS structure (11S-TS) is the geometry of the reac-
plex 11. TS structure 11S-TS gives the S-form of the tion coordinate involving the oxygen atoms of the
product (2a), while 11R-TS leads to the R configured peroxide molecule and the sulfur atom of 1a
counterpart. Formation of the S-product (11S-TS) re- (Figure 11). The reaction coordinate indicates cleav-
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age of the oxygen-oxygen bond (1.786 ꢆ) with a si- Indeed, in path Ib the R-product (12R-prod) is
multaneous formation of the oxygen-sulfur bond formed via a lower barrier (12R-TS) than the S-prod-
(2.210 ꢆ) involving one of the lone-pairs of the sulfur uct (12S-TS). Although path Ib favours the formation
ꢀ ꢀ
atom. The O O S angle is very close to 1808 impos- of the R-configured product, path Ia via reaction
ing a special geometrical constraint to the TS struc- channel 11!11S-TS!11S-prod represents the lowest
ture of the oxidation.[68] The major difference in the energy pathway alternative (Figure 8 and Figure 9).
structure of 11S-TS and 11R-TS is the conformation
As pointed out for 11S-TS and 11R-TS the oxida-
of the methyl group in the SMe functionality. The tion process in 12S-TS and 12R-TS the geometry of
lower stability of 11R-TS compared to 11S-TS can be the oxygen transfer is characterized by the closely
explained by the steric interaction between the linear arrangement of sulfur and peroxide oxygen
methyl group of 1a and Me3N ligand in 11R-TS. As atoms. Furthermore, the hydrogen bonding firmly
this interaction in not present in 11S-TS selective for- keeps 1a at the rear side of the TS structures in 12S-
mation of the S-sulfoxide (2a) product takes place. TS and 12R-TS.
The substrate position relative to the chiral tartrate
ligand is determined by hydrogen bonding. Of course,
ꢀ
in the absence of an N H group in the imidazole ring The Inner Sphere Mechanism of the Sulfoxidation
such hydrogen bonding cannot exist. This may explain (Path II)
the low selectivity obtained for the oxidation of 1b
(Table 1, entry 3). On the other hand the possible sub- In previous studies[2] mechanistic suggestions ap-
stituents at the C4 and C5 of the imidazole ring as peared for sulfoxidation of the imidazole sulfide-type
well as bulkier substituents on the sulfur are easily precursors (such as 1a) coordinated to titanium,
tolerated in 11S-TS, since these positions are not in- therefore we have briefly explored this reaction path
volved in any major steric interaction with the ligands as well. As we shown above (see above), 1a is readily
of the complex (Figure 11). This may explain the ex- coordinated to titanium, and thus complex 13
perimentally observed fact that in the presence of (Figure 10 and Figure 13) may also occur as reaction
bulky substituents at the C4, C5 (e.g., 1d–e and 1g–h) intermediate in the sulfoxidation reaction. However,
and SR (1c and 1h) positions the high enantioselectiv- the activation barrier (13R-TS) for the oxidation of
ity of the oxidation can be maintained (Table 1). The the coordinated sulfide (Figure 10) is much higher (by
reactions are highly exothermic (by 20–25 kcalmolꢀ1), 6–10 kcalmolꢀ1) than for the non-coordinated ones
and thus (as expected) the sulfoxidation process is ir- (such as for 11S-TS and 11R-TS, path Ia). The high
reversible.
activation barrier can be explained by dual geometri-
Path Ib: Reaction path Ib starts with complex 12, cal constraints in the TS structure 13R-TS
ꢀ ꢀ
which is less stable than complex 11 of path Ia. In (Figure 13). The oxidation process requires an O O
complex 12 the substrate molecule (1a) is bound to S angle which is close to 1808 and at the same time
the rear side of the tartrate molecule by hydrogen coordinative interactions between titanium and the
bonding. This mode of coordination in 12 renders 1a imidazole nitrogen. This leads to a much more strain-
to the opposite side of the complex compared to 11 ed TS state geometry for the inner-sphere mechanism
suggesting different selectivity for paths Ia and Ib. (path II) than for the out of sphere mechanistic path-
Figure 13. Selected calculated structures for path II (cf. Figure 11). The distances are given in ꢆ units and the Gibbs free
energy values and the total energy differences (in parentheses) are given in kcalmolꢀ1.
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Mechanism of the Asymmetric Sulfoxidation in the Esomeprazole Process
FULL PAPERS
Figure 14. Mechanism of the asymmetric sulfoxidation of 1a based on the above experimental and modelling results.
ways (paths Ia and Ib). Besides, in 13 and 13R-TS the Mechanism of the Asymmetric Sulfoxidation
ꢀ
N H group of imidazole is turned away from the tar-
trate ligand because of the coordination of the other Based on the above results obtained from the APCI,
nitrogen to titanium. Therefore, effective hydrogen NMR and DFT studies a catalytic cycle was con-
bonding between the imidazole ring and the tartrate structed (Figure 14). The APCI studies (see above) in-
ligand is not possible. As this type of hydrogen bond- dicate that added water facilitates the splitting of the
ing is essential for the asymmetric induction of the ox- binuclear complex 14 to a mononuclear analogue,
idation in 11S-TS, the selective sulfoxidation is also such as 15. According to the NMR studies (see
difficult to explain for the inner sphere mechanism.
above) the next step is coordination of the added
amine (such as 5a) to create the active intermediate
(16) of the catalytic cycle. The peroxide reagent coor-
dinates to titanium in an h2-fashion affording complex
17. The DFT studies show that at least two different
configurations (such as 11 and 12) are possible for
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complex 17 initiating two different reaction channels closely linear. Because of this constraint inner sphere
each (paths Ia and Ib). Starting from 17 the sulfoxida- oxidation of the imidazole sulfides (path II) is unlike-
tion reaction affords complex 19. The enantioselectiv- ly, which is confirmed by the DFT modelling studies.
ity of the sulfoxidation is determined in this step of
Assessment of the above mechanistic features af-
the catalytic cycle. We have localized a number of fecting the level of enantioselection in the oxidation
possible TS structures (11R-TS, 11S-TS, 12R-TS, 12S- of prochiral nitrogen containing heterocyclic com-
TS and 13R-TS) for the enantioselectivity determin- pounds, will hopefully inspire new laboratory as well
ing step of the process. According, to the modelling as industrial processes for the preparation of chiral
studies the lowest energy path corresponds to the sulfoxides.
11!11S-TS!11S-prod process. Therefore, we pro-
pose that the lowest energy path in the sulfoxidation
reaction proceeds via complex 18TS, which is the real- Experimental Section
istic analogue of model structure 11S-TS. In this com-
plex the S-Me group points away the titanium atom
inducing S-configuration on the sulfur in the oxida-
Sulfides 1a–1g[12,69–71] and racemic sulfoxides[12] (applied as
standards for the determination of the ee values) were pre-
pared according to the reported procedures. Unless other-
tion process (see above).
1
wise stated the H and 13C NMR spectra were recorded in
As pointed out in the modelling studies, the chiral
CDCl3 on Varian 300 or 400 MHz spectrometers. The chemi-
induction is governed by hydrogen bonding, interac-
cal shifts (ppm) were obtained by using CHCl3 as internal
ꢀ
tions between the N H group of the imidazole ring
and the chiral tartrate ligand. Another important geo-
metrical factor influencing the enantioselectivity is
the stereolectronic requirement[60] of the sulfoxidation
requiring a linear alignment of the peroxide oxygens
standard (1H NMR: 7.26 ppm; 13C NMR: 77.36 ppm). The
optical rotation data (c=g substance/100 mL solvent) were
obtained on a Perkin–Elmer 241 polarimeter. The HPLC
data was obtained on “Waters AcquityTM Ultraperformance
LC” instrument (for chromatographic conditions see the
corresponding entries).
ꢀ ꢀ
and sulfur atom (O O S angle) in the TS structure.
In complex 19 the oxygen of the sulfoxide group is co-
ordinated to titanium. The final step of the process is
decomplexation of the chiral sulfoxide product, such
as 2a, regenerating the catalyst.
General Procedure for Catalytic Oxidation of
Sulfides
To a solution of sulfide 1 (0.25 mmol) in toluene (0.5 mL),
water (0.001 mL, 0.055 mmol) and d-(ꢀ)-diethyl tartrate 4
(0.025 mL, 0.152 mmol) were added. This solution was
heated to 508C and stirred at this temperature for 15 min.
Then, titanium(IV) isopropoxide 3 (0.022 mL, 0.076 mmol)
was added; and the reaction mixture was kept at 508C for
45 min. Subsequently, the temperature was lowered (see
Table 1 for specific cases) followed by addition of diisopro-
pylethylamine 5a (0.013 mL, 0.076 mmol) and cumene hy-
Conclusions
The above studies have shown that the smallest subu-
nit of pyrmetazole (1h) required for the high level of
enantioselection in the esomeprazole process is an
imidazole ring. Methyl imidazole sulfide 1a could be
oxidized as selectively as its functionalized analogues, droperoxide
6 (0.1 mL of 2.5M solution in toluene,
0.25 mmol). The obtained reaction mixture was stirred for
the allotted times and temperatures (Table 1). The reaction
was then quenched by addition of water, followed by extrac-
tion with EtOAc (2ꢇ10 mL). The combined organic layers
were washed with brine (1ꢇ5 mL), then dried (MgSO4) and
concentrated under vacuum. The crude product (2) was pu-
rified by column chromatography over silica gel using an ap-
propriate ratio of pentane/EtOAc as eluent.
such as 1c–e and 1g–h. However, nitrogen substitution
of the imidazole ring leads to a major drop of the
enantioselectivity. APCI studies indicate that addition
of water to the reaction mixture of oxidation shifts
the equilibrium toward formation of mononuclear ti-
tanium species providing the catalytically active spe-
cies of the selective oxidation. According to our
NMR studies the added amine is able to coordinate
to titanium to create coordinatively saturated com-
2-Methyl
ACHTUNGTREN(NUNG sulfinyl)imidazole (2a): Sulfoxide 2a was pre-
pared according to the above general procedure, except that
plexes. Thus, the prochiral sulfides are not coordinat- additional 1 mL of toluene was added to the reaction mix-
ture after the addition of cumene hydroperoxide. The chiral
ed to titanium but to the chiral tartrate ligand by hy-
drogen bonding. In the absence of an N H group on
sulfoxide 2a was obtained as a white solid in 97% ee; yield:
ꢀ
1
62%. H NMR: d=7.18 (s, 2H), 3.04 (s, 3H); 13C NMR: d=
the imidazole ring, such coordination is not possible,
which is the probable explanation of the low enantio-
selectivity observed for oxidation of N-methyl ana-
logues 1b and 1f. The stereoelectronic effects of the
transfer of the oxygen atom from the peroxide re-
agent to the sulfur atom of the substrate impose an
important geometrical constrain to the TS structure
ꢀ ꢀ
146.5, 125.7, 40.8; [a]2D0: +73.3 (c 1.57, acetone). The ee was
determined by HPLC (Chiralpak AS column, isohexane/i-
PrOH, 90:10, flow rate 0.8 mLminꢀ1): tR (minor)=29.8 min,
tR (major)=31.5 min, l=238.7 nm; HR-MS (ESI): m/z=
137.0358, calcd. for [C4H6N2OS+Li]+: 137.0355. The abso-
lute configuration of 2a was determined by X-ray analysis.[51]
2-MethylACTHNUTRGENUG(N sulfinyl)-N-methylimidazole (2b): Sulfoxide 2b
of the complex, by rendering the O O S angle to was prepared according to the above general procedure,
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Mechanism of the Asymmetric Sulfoxidation in the Esomeprazole Process
FULL PAPERS
1
except that the reaction was carried out in toluene-d8. The
in 94% ee; yield: 63%. The H NMR data obtained for 2g
agree with the literature values given for its racemic form.[12]
1H NMR (CD3OD): d=7.50 (d, J=8.59 Hz, 1H), 7.07 (s,
1H), 6.91 (dd, J=2.49 Hz, 8.71 Hz, 1H), 3.78 (s, 3H), 3.08
(s, 3H); 13C NMR (CD3OD): d=159.9, 155.3, 140.2, 136.5,
119.4, 116.3, 99.1, 57.1, 41.9; [a]2D0: +45.7 (c 1.04, acetone).
The ee was determined by HPLC (Chiralcel OJ-H column,
hexane/i-PrOH, 90:10, flow rate 1.0 mLminꢀ1): tR (major)=
15.4 min; tR (minor)=19.9 min, l=302.8 nm; HR-MS
(ESI): m/z=211.0539, calcd. for [C9H10N2O2S+H]+:
211.0536,.
1
yield (33%) was determined by H NMR spectroscopy using
1
naphthalene as internal standard. The H NMR shifts were
1
determined from the crude reaction mixture. H NMR (tolu-
ene-d8): d=6.33 (d, J=1.2 Hz, 1H), 6.26 (brs, 1H), 3.27 (s,
3H), 2.71 (s, 3H). Addition of shift reagent [(S)-(+)-N-(3,5-
dinitrobenzoyl)-a-methylbenzylamine] showed that the
product is racemic (<2% ee).
2-BenzylACHTUNGTRENNUNG(sulfinyl)imidazole (2c): Sulfoxide 2c was pre-
pared according to the above general procedure, except that
additional 1 mL of toluene was added to the reaction mix-
ture after the addition of cumene hydroperoxide. The chiral
sulfoxide 2c was obtained as a white solid in 95% ee; yield:
Esomeprazole (2h): This product was prepared according
to the above general procedure except that it was isolated
as a potassium salt (78% yield and 97% ee) by addition of
1
61%. H NMR: d=11.59 (br s, 1H), 7.23 (m, 5H), 7.0 (m,
1
potassium methoxide to the reaction mixture. The H NMR
2H), 4.21 and 4.41 [d (AB-system), J=13.5 Hz, 2H];
13C NMR: d=144.7, 130.7, 130.6, 129.1, 128.9, 128.8, 61.2;
[a]2D0: ꢀ85.3 (c 1.04, acetone). The ee was determined by
HPLC (Chiralcel OJ-H column, hexane/i-PrOH 80:20, flow
rate 0.8 mLminꢀ1): tR (major)=7.0 min; tR (minor)=
8.7 min, l=246.9 nm. HR-MS (ESI): m/z=207.0584, calcd.
for [C10H10N2OS+H]+: 207.0587.
data obtained for 2h agree with the literature values.[2]
1H NMR (DMSO-d6): d=8.25 (s, 1H), 7.37 (d, J=8.6 Hz,
1H), 7.02 (d, J=2.6 Hz, 1H), 6.60 (dd, J=2.5 Hz, 8.4 Hz,
1H), 4.72 and 4.46 [d (AB system, J=12.7 Hz, 2H)], 3.75 (s,
3H), 3.70 (s, 3H), 2.21ACTHNUTRGNEUNG
(s, 6H); 13C NMR (DMSO-d6): d=
163.4, 161.8, 153.7, 151.9, 149.1, 147.0, 141.6, 126.5, 124.9,
117.5, 109.0, 99.4, 59.7, 55.2, 48.6, 12.9, 11.3; [a]2D0: +30.1 (c
1.0, H2O); Lit.[2] [a]D20: +30.5 (c 1.0, H2O) for (S), 99.5% ee.
The ee was determined by HPLC (Chiralpak AD-H column,
hexane/i-PrOH/AcOH, 50:50:0.1, flow rate 0.6 mLminꢀ1):
tR (minor)=9.9 min; tR (major)=11.7 min, l=300.3 nm.
4,5-Diphenyl-2-methylACTHNUGRTENUNG(sulfinyl)imidazole (2d): Sulfoxide
2d was prepared according to the above general procedure,
except that additional 1 mL of toluene was added to the re-
action mixture after the addition of cumene hydroperoxide.
The chiral sulfoxide 2d was obtained as a white solid in 80%
1
ee; yield: 50%. H NMR (DMSO-d6): d=7.48 (d, J=6.9 Hz,
4H), 7.35 (m, 6H), 3.09 (s, 3H); 13C NMR (DMSO-d6): d=
148.4, 133.2, 129.2, 128.5, 39.5 (the quaternary carbons are
not visible due to line broadening); [a]2D0: +37.6 (c 0.75,
CHCl3). The ee was determined by HPLC (Chiralpak AD-H
column, hexane/i-PrOH, 95:5, flow rate 1.1 mLminꢀ1): tR
(minor)=8.5 min; tR (minor)=9.4 min, l=270.2 nm; HR-
MS (ESI): m/z=283.0897, calcd. for [C16H14N2OS+H]+:
283.0900.
General Procedure for Preparation of the APCI/MS
Sample
(a) Reaction mixture in the absence of added water: Diethyl
tartrate 4 (0.013 mL, 0.076 mmol) and CHCl3 (0.5 mL) were
heated to 508C for 15 min. Then, titanium(IV) isopropoxide
3 (0.011 mL, 0.038 mmol) was added; and the reaction mix-
ture was kept at 508C for 45 min. After cooling the reaction
mixture to room temperature the solution was diluted with
5 mL of CHCl3. The turbid solution was centrifuged and the
supernatant solution was used for analysis.
2-MethylACHTUNGTRENNUNG(sulfinyl)benzimidazole (2e). This product was
prepared according to the above general procedure afford-
1
ing 2e as a white solid in 98% ee; yield: 65%. The H NMR
data obtained for 2e agree with the literature values given
for its racemic form.[12] 1H NMR: d=7.78, (br s, 1H), 7.58
(br s, 1H), 7.31 (m, 2H), 3.18 (s, 3H); 13C NMR: d=153.9,
143.9, 134.9, 124.7, 123.5, 120.4, 112.5, 41.6; [a]2D0: +39.3 (c
5.53, acetone)¸ Lit.[72] [a]2D0: ꢀ20.8 (c 1.0, acetone) for (R),
61% ee. The ee was determined by HPLC (Chiralcel OJ-H
column, isohexane/i-PrOH, 95:5, flow rate 0.8 mLminꢀ1): tR
(major)=20.9 min; tR (minor)=26.5 min, l=280.2 nm;
HR-MS (ESI): m/z=181.0432, calcd. for [C8H8N2OS+H]+:
181.0430.
(b) Reaction mixture in the presence of added water:
This sample was prepared according to the above general
procedure except that the water (1 mL) was added.
Synthesis of Complexes 9 and 10
To a solution of 1a (0.25 mmol) in CHCl3 (0.5 mL), water
(2.5 mL) and d-(ꢀ)-diethyl tartrate 4 (0.013 mL, 0.076 mmol)
was added. This solution was heated to 508C and stirred for
2-MethylACHTUNGTRENNUNG(sulfinyl)-N-methyl-benzimidazole (2f): This
product was prepared according to the above general proce-
15 min. Then, titanium(IV) isopropoxide
3 (0.011 mL,
dure affording 2f as a white solid in <2% ee; yield: 48%.
0.038 mmol) was added; and the reaction mixture was kept
at 508C for 45 min. Subsequently, the reaction mixture was
cooled to room temperature and ether (6 mL) was added.
The white precipitate (9) was separated by centrifugation.
1H NMR (CD3OD): d=7.34 (s, 2H), 4.55 (s, 2H), 4.26 (q,
J=7.08, 4H), 2.68 (s, 3H), 1.32 (t, J=7.02, 6H); 13C NMR
(CD3OD): d=171.53, 142.25, 122.07, 72.41, 61.14, 16.96,
13.06.
1
The H NMR data obtained for 2f agree with the literature
values given for its racemic form.1 1H NMR: d=7.82 (m,
1H), 7.42 (m, 2H), 7.36 (m, 1H), 4.14 (s, 3H), 3.26 (s, 3H);
13C NMR: d=152.2, 141.9, 137.1, 124.8, 123.7, 121.2, 110.1,
39.3, 31.1; HR-MS (ESI): m/z=195.0588, calcd. for
[C9H10N2OS+H]+: 195.0587.
2-MethylACHTUNGTRENNUNG(sulfinyl)-5-methoxybenzimidazole (2g): Sulfox-
ide 2g was prepared according to the above general proce-
dure, except that additional 1 mL of toluene was added to
the reaction mixture after the addition of cumene hydroper-
oxide. The chiral sulfoxide 2g was obtained as a gummy gel
To complex 9 in CDCl3 one equivalent of 5a was addded
and the sample (10) was studied by 13C NMR spectrosco-
py.13C NMR (CDCl3) for 10: d=171.90, 141.69, 72.39, 62.68,
51.79, 41.28, 19.75, 18.72, 16.81, 14.45.
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[13] D. M. Tavish, M. M. Buckley, R. C. Heel, Drugs 1991,
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Oxidation of 1a with 9 as Catalyst
A chloroform solution (0.25 mL) of complex 9 (0.016 g,
0.038 mmol), 1a (0.010 g, 0.087 mmol), 5a (0.005 mL,
0.038 mmol) and water (1 mL) was stirred for 1 h at 508C.
Subsequently, the temperature was lowered to ꢀ208C fol-
lowed by addition of cumene hydroperoxide 6 (0.05 mL of
2.5M solution in CHCl3, 0.125 mmol) and CHCl3 (0.5 mL)
and the obtained reaction mixture was stirred for 6 h. Then,
the reaction was quenched with water, followed by addition
of EtOAc (5 mL) and extraction with water (2ꢇ5 mL).
After evaporation the crude product (2a) was purified by
column chromatography over silica gel using an appropriate
ratio of pentane/EtOAc as eluent; yield:45% yield, 79% ee).
The ee was determined by HPLC (Chiralpak AS column,
isohexane/i-PrOH, 90:10, flow rate 0.8 mLminꢀ1): tR
(minor)=29.8 min; tR (major)=31.5 min, l=238.7 nm.
Supporting Information
Cartesian coordinates for species 11–13, NMR spectra for
2a–i and complex 9 and simulations of the isotope patterns
of complexes 7 and 8 are available as Supporting Informa-
tion.
[23] S. Padmanabhan, R. C. Lavin, G. J. Gurant, Tetrahe-
dron: Asymmetry 2000, 11, 3455.
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