Efficient chemoenzymatic dynamic kinetic resolution of 1-heteroaryl ethanols

Article abstract of DOI:10.1021/jo901987z

(Chemical Equation Presented) The scope and limitation of the combined ruthenium-lipase induced dynamic kinetic resolution (DKR) through O-acetylation of racemic heteroaromatic secondary alcohols, i.e., 1-heteroaryl substituted ethanols, was investigated. After initial screening of reaction conditions, Candida antarctica lipase B (Novozyme 435, N435) together with 4-chloro-phenylacetate as acetyl-donor for kinetic resolution (KR), in conjunction with the ruthenium-based Shvo catalyst for substrate racemization in toluene at 80°C, enabled DKR with high yields and stereoselectivity of various 1-heteroaryl ethanols, such as oxadiazoles, isoxazoles, 1H-pyrazole, or 1H-imidazole. In addition, DFT calculations based on a simplified catalyst complex model for the catalytic (de)hydrogenation step are in agreement with the previously reported outer sphere mechanism. These results support the further understanding of the mechanistic aspects behind the difference in reactivity of 1-heteroaryl substituted ethanols in comparison to reference substrates, as often referred to in the literature.

Full text of DOI:10.1021/jo901987z

pubs.acs.org/joc
Efficient Chemoenzymatic Dynamic Kinetic Resolution
of 1-Heteroaryl Ethanols
†
Karl S. A. Vallin, David Wensbo Posaric,* Zdenko Hamersak, Mats A. Svensson,
,‡
§
†
ꢀ
and Alexander B. E. Minidis*,†
†
€ € € €
Medicinal Chemistry, CNS & Pain Control, AstraZeneca R&D Sodertalje, SE-15185 Sodertalje, Sweden.
‡Current address: Stro€m & Gulliksson, Ja€rnva€gsg. 3, SE-252 24 Helsingborg, Sweden. §Current address:
9
ꢀ ꢁ ꢀ
Department of Organic Chemistry and Biochemistry, Ruder Boskovic Institute, Bijenicka c. 54,
P.O. Box 108, 10002 Zagreb, Croatia.
alexander.minidis@astrazeneca.com, david.wensbo@sg.se
Received September 15, 2009
The scope and limitation of the combined ruthenium-lipase induced dynamic kinetic resolution (DKR)
through O-acetylation of racemic heteroaromatic secondary alcohols, i.e., 1-heteroaryl substituted
ethanols, was investigated. After initial screening of reaction conditions, Candida antarctica lipase B
(Novozyme 435, N435) together with 4-chloro-phenylacetate as acetyl-donor for kinetic resolution
(KR), in conjunction with the ruthenium-based Shvo catalyst for substrate racemization in toluene at
80 °C, enabled DKR with high yields and stereoselectivity of various 1-heteroaryl ethanols, such as
oxadiazoles, isoxazoles, 1H-pyrazole, or 1H-imidazole. In addition, DFT calculations based on a
simplified catalyst complex model for the catalytic (de)hydrogenation step are in agreement with the
previously reported outer sphere mechanism. These results support the further understanding of the
mechanistic aspects behind the difference in reactivity of 1-heteroaryl substituted ethanols in
comparison to reference substrates, as often referred to in the literature.
Introduction
1,2,4-triazoles, in which the heterocycle simultaneously is ser-
ving as a masked amino group of primary amines1,2 and amino
acids,3 which have been used as chiral inducers in stereoselective
alkylations. Five-membered heterocycles are furthermore pre-
sent in a plethora of compounds, both natural and synthetic in
origin, that bear well-defined biological activities.4-18
Enantiomerically pure 1-heteroaryl ethanols 1, wherein
the heteroaryl moiety Q constitutes five-membered nitrogen-
containing heteroaromatics, are of broad general interest as
synthetic intermediates, metal chelators and ligands, chiral
auxiliaries, and potential drug leads or scaffolds.
The heteroatoms of 1 entail and enrich the molecule with
requisite properties for the interaction with proteins, for the
ability of it to coordinate to metals, and for the prospect of the
heteroaromatic part Q to function as a masked equivalent of
other functional groups. Furthermore, the asymmetry of 1 is
essential for its use as a chiral auxiliary and is often desirable
for the selective and optimal interaction with proteins, e.g.,
receptors and enzymes. Compounds 1 are for example chiral
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Published on Web 10/27/2009
DOI: 10.1021/jo901987z
r
2009 American Chemical Society

Vallin et al.
JOCArticle
on analogous KRs, where Qof 1 is represented by benzene41-43
or by heterocycles such as furan,42 thiophene,44,45 and pyri-
dine,46 are more frequent. The fact that one enantiomer can be
obtained in only a 50% maximum yield from the racemate by
any conventional KR has brought much attention to the
concept of dynamic kinetic resolution (DKR),47 where a
theoretic yield of 100% can be reached. In DKR, the enantio-
mer discriminated by the irreversible KR process is simulta-
neously racemized, or inverted, by a second process run in situ.
Since the second process is in equilibrium with the first, a full
overall conversion is achievable (Scheme 1).
FIGURE 1. Q is a five-membered heterocyclic ring.
Thus, heteroaryl ethanols 1 constitute a highly interesting
small molecular scaffold in drug research structural optimiza-
tion. Synthetic approaches often are limited to the use of a
chiral starting material,19-22 if not on tedious chiral separation
alone. General methodologies for the construction of various
chiral heterocyclic compounds 1 from either achiral or race-
mic precursors are therefore desired. Previous reports on the
former include stereoselective reductions5,20,23-30 and the use of
biocatalysts in the form of either isolated enzymes or whole
cells.25,31-34 Earlier literature describing the latter comprise
resolution by chromatographic separation,35 enzymatic de-
racemization,36 and kinetic resolution (KR) by selective oxi-
dation of one of the enantiomers.37,38 To our knowledge, only
two reports on successful KR through lipase-catalyzed acyla-
tion of racemic alcohols 1 have been published, both of them
including a thiazole as the heterocyclic moiety Q.39,40 Reports
SCHEME 1. DKR versus KR
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Other highly efficient ruthenium precatalysts include 3
and 4.55-57 Recently, Park et al. reported on the robust
racemization catalyst 5.58 In addition, Trauthwein et al.
identified a stable racemization catalyst, constituting a
[Ru(cymene)Cl2]2 complex bearing chelating aliphatic dia-
mines.59 These and others have been recently reviewed.60,61
SCHEME 2. Synthesis of 5-Aryl Substituted 1,2,4-Oxadiazolesa
ꢁ
Mechanistic studies by the groups of Casey et al. and Lledos
et al.62a,b showed compelling evidence for a concerted hydro-
gen transfer mechanism (vide infra).
Encouraged by the recent advancements in DKR of
secondary alcohols, we envisioned this methodology as a
viable approach to chiral alcohols 1, starting from the
corresponding racemic mixtures. In this paper, we wish to
report our results on DKR, employing a lipase in combina-
tion with the Shvo catalyst (2), with focus on racemic
heterocyclic alcohols encompassed by 1, including substrates
hitherto not or rarely found in literature. Since such sub-
strates are not as readily accessible as the typical model
substrates employed in exploratory DKR, we took advan-
tage of a computational model for the design of substrates
and for an estimate of their performance in the DKR. The
correlation between these findings and the experimental
results is discussed.
aReagents and conditions: (i) pyridine, DCM, 0 °C to rt; (ii) reflux in
EtOH; (iii) AcCl, 10 mol % HOBt, TEA, DCM, 0 °C to rt.
SCHEME 3. Synthesis of 3-Aryl Substituted 1,2,4-Oxadiazoles
from L-(þ)-Lactic Acida
Results and Discussion
Synthesis of Racemic 1-Heteroaryl Ethanols. Initially, we
desired a set of representative heterocyclic racemic substrates
as well as selected O-acetylated derivatives thereof as analy-
tical references. In each case, the synthetic route of choice
was much dictated by the adherent heterocycle as described
below.
The 5-aryl substituted 1,2,4-oxadiazole (rac)-9 was synthe-
sized by selective O-benzoylation of N-hydroxy-amidine 7,
followed by ring closure of the acyclic intermediate 8 by
heating in ethanol as described in Scheme 2. The correspond-
ing racemic acetate (rac)-10 was subsequently obtained by
conventional acetylation.
As independent enantiomerically pure reference materials
with known absolute configuration, the chiral 3-aryl sub-
stituted 1,2,4-oxadiazole (S)-13 and the corresponding
acetylated derivative (S)-14 were synthesized from L-(þ)-
lactic acid as shown in Scheme 3. Benzonitrile 11 was
first converted to N-hydroxy-amidine 12 by treatment with
hydroxyl amine in ethanol, followed by DCC-mediated
coupling with L-(þ)-lactic acid and subsequent ring closure
to yield (S)-13. Under these conditions, no racemization of
(S)-13 or precursors could be noted. Oxidation of (S)-13 with
PCC yielded ketone 15, which was reduced back with sodium
aReagents and conditions: (i) H2NOH HCl, NaOH, reflux in EtOH;
3
(ii) L-(þ)-lactic acid, HOBt (10 mol %), DCC, DMSO, rt, then reflux
in EtOH; (iii) PCC, DCM, rt; (iv) NaBH4, THF, rt; (v) AcCl, HOBt
(10 mol %), triethylamine, DCM, 0 °C to rt.
borohydride to give (rac)-13. The corresponding acetates
(S)-14 and (rac)-14 were obtained by acetylation of (S)-13
and (rac)-13, respectively.
The 1,3,4-oxadiazole alcohol (rac)-18 was conveniently
obtained by displacing the chloride of (rac)-16 with potas-
sium acetate in DMF, followed by hydrolysis of the formed
acetate (rac)-17 as described in Scheme 4. The starting
material (rac)-16 was prepared from 3-chlorobenzohydra-
zide in two steps.63 The 5-(het)aryl substituted isoxazoles
(rac)-21 and (rac)-22 were synthesized by treatment of the
corresponding commercially available aldehydes 19 and 20,
respectively, with methyllithium.63
€
(55) Martin-Matute, B.; Edin, M.; Bogar, K.; Backvall, J.-E. Angew.
Chem., Int. Ed. 2004, 43, 6535–6539.
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Angew. Chem., Int. Ed. 2002, 41, 2373–2376.
€
(57) Martin-Matute, B.; Edin, M.; Bogar, K.; Kaynak, F. B.; Backvall,
J.-E. J. Am. Chem. Soc. 2005, 127, 8817–8825.
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2005, 7, 4523–4526.
(59) Riermeier, T. H.; Gross, P.; Monsees, A.; Hoff, M.; Trauthwein, H.
Tetrahedron Lett. 2005, 46, 3403–3406.
(60) Kamal, A.; Azhar, M. A.; Krishnaji, T.; Malik, M. S.; Azeeza, S.
Coord. Chem. Rev. 2008, 252, 569–592.
(61) Ahn, Y.; Ko, S.-B.; Kim, M.-J.; Park, J. Coord. Chem. Rev. 2008,
252, 647–658.
Oxime 24 was prepared by treatment of aldehyde 23 with
hydroxyl amine (Scheme 5).64 Pyridyl oximes 25-27 were
commercially available. Hydroximoyl chlorides 28-31 were
(62) (a) Casey, C. P.; Singer, S. W.; Powell, D. R.; Hayashi, R. K.;
Kavana, M. J. Am. Chem. Soc. 2001, 123, 1090–1100. (b) Comas-Vives, A.;
ꢁ
Ujaque, G.; Lledos, A. Organometallics 2007, 26, 4135–4144.
(63) Wensbo, D. et al. WO2004014881(A2), 20040219.
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9330 J. Org. Chem. Vol. 74, No. 24, 2009

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SCHEME 6. Synthesis of a 3-Aryl Substituted Isothiazolea
SCHEME 4. Synthesis of 1,3,4-Oxadiazoles and 5-(Het)aryl
Substituted Isoxazolesa
aReagents and conditions: (i) ClCOSCl, toluene, 100 °C; (ii) but-3-yn-
2-one, MW irradiation, 120 °C; (iii) NaBH4, THF.
aReagents and conditions: (i) KOAc, DMF, rt; (ii) KOH, MeOH, rt;
(iii) MeLi, THF, rt.
Oxazole (rac)-46 and imidazole (rac)-43 were obtained by
lithiation of the corresponding unsubstituted derivatives 45
and 42, respectively, followed by trapping with acetaldehyde
as described in Scheme 7. The SEM group, employed to
direct lithiation at the imidazole ring of 42, was removed by
treatment with TBAF to yield (rac)-44.46
SCHEME 5. Synthesis of 3-Aryl Substituted Isoxazole Deriva-
tivesa
SCHEME 7. Synthesis of Imidazoles and Oxazole Derivativesa
aReagents and conditions: (i) H2NOH HCl, H2O, EtOH; (ii) BnN-
3
Me3þICl4-, DCM; (iii) 3-butynol, Et3N, EtOH. bIsolated as the HCl salt.
aReagents and conditions: (i) NaH, SEM-Cl, DMF; (ii) n-BuLi, THF,
-78 °C, then acetaldehyde, -78 °C to rt; (iii) TBAF, THF, rt.
synthesized by chlorination of oximes 24-27 according to
the procedure of Kanemasa et al.65 The corresponding nitrile
oxides, generated in situ by treatment of these with triethyl-
amine, underwent cycloaddition with 3-butynol to furnish
the 3-(het)aryl substituted isoxazoles (rac)-32 to (rac)-35,
respectively.66
The 3-aryl substituted isothiazole (rac)-40 was prepared
starting from amide 36 as described in Scheme 6.43,45 Initial
treatment with chlorocarbonylsulfenyl chloride generated
oxathiazolone 37 in good yield. 1,3-Dipolar cycloaddition
of the corresponding unstable nitrile sulphide, obtained by
thermal decarboxylation of 37, with 3-butyn-2-one gave a
mixture (73:27, respectively) of regioisomers 38 and 39.44
These were easily separated by chromatography, and ketone
38 was subsequently reduced with sodium borohydride to
yield alcohol (rac)-40. Attempted cycloaddition employing
the relatively more electron-rich 3-butyn-2-ol as reagent
resulted in formation of 4-chlorobenzonitrile as the only
isolable product.
Evaluation of Lipases and Acyl Donors for KR. The com-
mercially available immobilized lipases Candida antarctica lipase
B (Novozyme 435, N435),67 Mucor miehei (MM),68 Pseudomonas
cepacia (PC),41 and Candida cylindracea (CC)69 have all been
used in KR of substrates in which the sterically less demanding
substituent, in analogy to 1, is composed of a methyl group and
were therefore considered as suitable candidate lipases. The three
acyl donors isopropenyl acetate 47, 4-chlorophenyl acetate 48,and
3-acetoxypyridine 49 were chosen for evaluation (Figure 3).
FIGURE 3. Acyl donors.
(67) Ohtani, T.; Nakatsukasa, H.; Kamezawa, M.; Tachibana, H.;
Naoshima, Y. J. Mol. Catal B: Enzym. 1998, 4, 53–60.
(68) Santaniello, E.; Casati, S.; Ciuffreda, P.; Gamberoni, L. Tetra-
hedron: Asymmetry 2004, 15, 3177–3179.
(65) Kanemasa, S.; Matsuda, H.; Kamimura, A.; Kakinami, T. Tetra-
hedron 2000, 56, 1057–1064.
(66) Demina, O. V.; Vrzheshch, P. V.; Khodonov, A. A.; Kozlovskii,
V. I.; Varkholomeev, S. D. Bioorg. Khim. 1995, 21, 933–940.
(69) Medio-Simon, M.; Gil, J.; Aleman, P.; Varea, T.; Asensio, G.
Tetrahedron: Asymmetry 1999, 10, 561–566.
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The former two were chosen because of their wide use in
KRs and DKRs, respectively, and the latter because of an
early report by Kitajima et al. on the successful use of
heterocyclic acyl donors in KRs.70 We reasoned that the
use of 49 could be advantageous due to its relatively higher
water solubility and polarity as compared to that of 48,
which is occasionally difficult to separate from the product
and in addition generates a toxic side product, p-chloro-
phenol.53,71 Screening of the candidate lipases in all com-
binations with the acyl donors 47-49 in KR of the
1,2,4-oxadiazole (rac)-9 as substrate in toluene at 30 °C
was performed (Scheme 8, Figures 4 and 5).
despite prolonged reaction times. 48 and 49 were found to be
comparable as acyl donors, and both were slightly more
efficient, in terms of reaction rate, as compared to 47. In
order to confirm the efficiency of N435 on a preparative
scale, (rac)-9 was subjected to KR by employment of this
lipase in combination with 47 as acyl donor for 72 h in
toluene at ambient temperature. (S)-9 and (R)-10 were upon
isolation each obtained in a 49% yield, each with a high
optical purity.
Dynamic Kinetic Resolution. As guided by the results from
the KR study, initial DKR experiments with (rac)-9 (0.10
mmol/mL solvent) were conducted using N435 (3.0 mg/mL)
as the selected lipase at 70 °C in toluene, in the presence of
2.0 mol % of the Shvo catalyst (2) and 3.0 equiv of the acyl
donor (48 or 49). A 50% conversion of the substrate was
observed in less than 3 h using either 48 or 49 as acyl donor.
In the former case, a 72% conversion was achieved after
48 h, whereas in the latter case the reaction never got beyond
50% conversion even after 120 h. These results indicate a
deactivation of the Shvo catalyst (2) when employing 49 as
acyl donor. We speculate that 49 in itself or, alternatively,
pyridin-3-ol formed from 49 may be responsible for this
deactivation by coordination to ruthenium. The results are
furthermore indicative of a fast initial consumption of the
R-alcohol by acetylation and of a comparably significantly
slower racemization process. In order to get more com-
parable kinetics between these two processes, the reaction
temperature and the stoichiometry of the racemization
catalyst were increased to 80 °C and 5.0 mol %, respectively,
while the amount of the lipase N435 was diminished to
2.0 mg/mL. The 4-chlorophenol, generated when using 48
as the acyl donor, tended to coelute with the desired acety-
lated products upon purification by chromatography. We
solved this issue by carrying out an alkaline wash (1.0 M
NaOH) of the crude product prior to further purifications.
These reaction settings and this workup procedure were
used in all further experiments, which are summarized in
Tables 1 and 2.72
SCHEME 8. Kinetic Resolution of (rac)-9 by Lipase Catalysed
Acetylationa
aReagents andconditions:(rac)-9(0.10mmol/mL), lipase(30mg/mmol
of (rac)-9), acyl donor (2.0 equiv), toluene, 30 °C.
From the results summarized in Table 1, it can be
concluded that N435 is a highly stereoselective biocatalyst
with high acceptance for substituted heterocyclic sub-
strates. In general, the R-enantiomers of the racemic
substrates in this study were selectively and effectively
acetylated, as indicated by yields close to 50% or greater,
with high enantiomeric purities of the products. One out-
standing exception is represented by the imidazole
(substrate 44, entry 16), where no acetylated product
(R)-62 could be detected. Interestingly, the corresponding
N-SEM substituted imidazole (rac)-43 proved to be an
excellent substrate (entry 15). The absolute stereochemistry
of the product (R)-14 (entry 1) was confirmed by comparing
with independently synthesized (S)-14 and (rac)-14
(Scheme 3) and thereby found to be in accordance with
FIGURE 4. Substrate conversion profiles in KR of (rac)-9 utilizing
the following combinations of lipase/acyl donor: (a) N435/48;
(b) N435/49; (c) N435/47; (d) PC/48.
FIGURE 5. Product (R)-10 enantiomeric excess profiles in KR of
(rac)-9 using the following combinations of lipase/acyl donor:
(a) N435/48; (b) PC/48.
(70) Keumi, T.; Hiraoka, Y.; Ban, T.; Takahashi, I.; Kitajima, H. Chem.
Lett. 1991, 1989–92.
(71) Verzijl, G. K. M.; de Vries, J. G.; Broxterman, Q. B. Tetrahedron:
Asymmetry 2005, 16, 1603–1610.
(72) Three equivalents of acyl donor in the DKR were used due to the
properties of the pyridine based donor 49. All subsequent reactions with
48 were, for ease of comparison, also run with 3 equiv of donor instead of
2 equiv, as used in the KR, which nevertheless allowed determining the
important relative differences between various substrates.
N435 proved to be the most suitable lipase irrespec-
tive of the acyl donor employed, with an E-value greater
than 200.68,69 In comparison, the E-value for PC was only 6
(Figures 4 and 5).
In this application, MM and CC proved to be of limited
use, as only trace amounts of the product could be detected
9332 J. Org. Chem. Vol. 74, No. 24, 2009

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TABLE 1. DKR of Racemic 1-Heteroaryl Ethanolsa
aReaction conditions: substrate (0.1 mmol/mL), acyl donor 48 (3.0 equiv), Shvo catalyst (2) (0.05 equiv), lipase N435 (2.0 mg/mL), toluene, 80 °C
under argon. bDetermined by chiral HPLC. Entry 1 is estimated as a result of uncomplete baseline separation. c2,4-Dimethyl-3-pentanol (1.0 equiv) was
added after 24 h. dNo reaction.
the predictive rule stating a preference of the lipase to
accommodate the R-enantiomer.73
It is known that ketones can be formed by ruthenium-
catalyzed dehydrogenation of secondary alcohols and that
this reaction can be suppressed by an added hydride donor,
such as a sacrificial alcohol (e.g., 2,4-dimethyl-3-pentanol),
or under a hydrogen atmosphere.74,75 Indeed, addition of
2,4-dimethyl-3-pentanol to the reaction mixture of isoxazole
(rac)-35 (entry 10) at the 24 h time point (100% conversion,
54% yield) resulted in improved yield and mass balance at
the 48 h time point (100% conversion, 82% yield).
Although the KR component of the DKR of these hetero-
cyclic substrates is a robust process, the indispensable
ruthenium-catalyzed racemization was found to be more
substrate-dependent in contrast to typical model substrates
and thus warrants focus in the discussion of the obtained
results. The outcome of the experiments may be divided into
three categories:
(1) High conversion and high yield, which is indicative of a
well working racemization with no or minimal competing
side reactions. The 3-aryl isoxazole (entry 8) and the 1-aryl
pyrazole (entry 14) represent heterocycles belonging to this
group of substrates.
(2) High conversion and medium yield (poormassbalance),
as observed for several substrates (entries 1-4, 6, 7, 9, 10, and
13), suggests a significant competing side reaction. Ketones,
corresponding to the respective secondary alcohol substrates,
were detected as the major byproduct (entries 6, 9, 10, 13, 15).
These results are in accordance with a mechanism in
which ruthenium-catalyzed dehydrogenation is highly favo-
red over reduction of the intermediate ketone, where the racemi-
zation is occurring under ruthenium catalysis (Scheme 9). This
dehydrogenation/reduction balance, however, may be altered
by the intervention of a hydride donor to enable or improve
a DKR as shown in the example above. The substrates in
this category are seemingly either favoring the dehydrogenation
or preventing the corresponding reduction.
€
(74) Edin, M.; Steinreiber, J.; Backvall, J.-E. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5761–5766.
€
(75) Pamies, O.; Backvall, J.-E. Adv. Synth. Catal. 2001, 343, 726–731.
(73) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia,
L. A. J. Org. Chem. 1991, 56, 2656–2665.
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Vallin et al.
JOCArticle
TABLE 2. DKI of S-Alcoholsa
took place (entries 1, 2, and 6, Table 1), were selected for DKI
experiments (Table 2). It is interesting to compare the results
obtained from the 5-aryl substituted 1,2,4-oxadiazole (S)-
9 (entry 1) with those from the 3-aryl substituted regioisomer
(S)-13 (entry 2). Although (S)-9 underwent DKI, albeit in a
low yield and with poor ee, no R-acetate could be obtained
from (S)-13 despite a prolonged reaction time. Instead,
under these forcing conditions, the S-acetate was formed in
enantiomeric excess. DKI of isoxazole (S)-22 resulted in a
low yield of the R-acetate, but with high ee (entry 3). The low
mass balance in this case resulted from pronounced ketone
formation. This low racemazation is nevertheless enough to
drive a DKR; see Table 1, entry 6.76
The results summarized in Tables 1 and 2 reveal structural
features that are of importance for the success of the race-
mization and thereby for the DKR of heterocyclic sub-
strates. It is clear, as expected, that the nature of the
heterocycle, to which the chiral center of the ethanol resi-
due is attached, is of importance. Its close proximity to the
hydroxyl group permits electronic interaction, as well as a
possibility of intramolecular complex formation, with any of
the intermediates belonging to the catalytic cycle of the
racemization. For example, by substituting the isoxazole
(entry 8, Table 1) for an isothiazole ring (entry 13, Table 1),
a significant drop in yield (from 96% to 50%) is observed due
to increased ketone formation. A similar observation is made
for the regioisomeric isoxazole (entry 6, Table 1) where the
adjacent heteroatom is oxygen and not nitrogen. Interest-
ingly, various remote structural features were also noted
to affect the racemization: the presence of a remote bromo
substituent has a negative effect as compared to a chloro
substituent (compare entries 8 and 9, Table 1). A remote 3- or
4-pyridyl substituent blocks racemization as well as de-
hydrogenation, while a remote 2-pyridyl substituent allows
dehydrogenation of the substrate (compare entries 10-12,
Table 1). In the latter case an effective DKR is accomplished
by the addition of 2,4-dimethyl-3-pentanol.
aReaction conditions: see Table 1. bDetermined by chiral HPLC.
cThe S-acetate was obtained as major isomer.
SCHEME 9. Catalyst Activation (top) and Hydrogen Transfer
(below)
Calculations
Inspired by and based on the mechanistic work by Casey’s
group and Lledos et al.,62a,b we believed our substrates to fit
ꢁ
the concerted hydrogen transfer model (Scheme 9). At the
same time, we envisioned a crude predictive model for
substrate activity, which yet allowed a good approximation
of the relative energies at the transition state of the transfer
hydrogenation step. To accomplish this, we truncated the
catalyst by replacing the phenyl groups with hydrogens
(Figure 6) and calculated, for comparison, two examples
with the complete catalyst.77,78
(3) Medium conversion and medium yield (with concur-
ring good mass balance) is the expected result in the case of a
functional and stereoselective acetylation reaction, but with
a sluggish racemization process and without significant
dehydrogenation. The outcome of the reaction is thus similar
to what is expected from a KR. 1,3,4-Oxadiazole (rac)-18
(entry 5), oxazole (rac)-46 (entry 17), and the 3- and 4-pyridyl
substituted isoxazoles (rac)-34 and (rac)-33 (entries 11 and
12, respectively) are substrates that are more or less inert to
catalysis by 2. Accordingly, the corresponding S-alcohols
were the major components detected besides the desired
R-acetates in these cases. If the ruthenium catalyst effectively
mediates racemization of the alcohol, it should be indepen-
dent of the optical purity of scalemic (S-configured) sub-
strate. Therefore, based on any given DKR of the present
study, the outcome of the reaction should be comparable in
the case of a dynamic kinetic inversion (DKI), i.e., where an
S-alcohol, instead of the corresponding racemate, is con-
verted to the corresponding R-acetate. Thus, three sub-
strates, where doubt existed on whether or not a true DKR
(76) When using substrate 22 with the more recent catalyst 4 developed by
Backvalls group, no racemization at all was observed after 24 h at room
57
€
temperature. Private communication from Prof. J. E. Backvall.
€
(77) For verification and reference sake, we made test calculations with
the phenyls present and found that the nature of the intermediates and the
transition state does not change and the activation energy was just slightly
increased (approximately 2 kcal/mol). We believe that when comparing
different ligands of similar size as our substrates, the relative difference will
not be significant.
(78) Calculations where performed using the Jaguar program (v7.5) from
Schrodinger Inc. using the B3LYP functional and the lacvp** basis set. The
relative energies includes solvent effects using benzene and the PBF approxi-
mation. All structures are fully optimzed (in gas phase) and characterized
using Hessian calculation and normal-mode analysis. All reported relative
energies includes entropy effects and solvent effects.
9334 J. Org. Chem. Vol. 74, No. 24, 2009

Vallin et al.
JOCArticle
absolute predictions cannot be made, the corresponding
calculation may be used for predicting a qualitative outcome
of a DKR for a given substrate.
Conclusion
FIGURE 6. “Truncated” catalyst.
In summary, we have demonstrated efficient DKR of a
range of substituted heterocyclic racemic ethanols, hence
extending the tool box for synthesis of valuable chiral sub-
strates and intermediates. As of now, the reaction conditions
We then optimized the key intermediates and the transi-
tion state and computed the relative energies (Figure 7) of the
typical (de)hydrogenation step (Table 3).
€
are limited to the first generation Backvall-type of system,
employing Novozyme, the Shvo catalyst, and 4-chlorophenyl
acetate. In addition, we have presented theoretical data in the
form of density functional calculations. The results therefrom
are in alignment with the concerted hydrogen transfer me-
ꢁ
chanism proposed by Lledos, Ujaque, and Comas-Vives and
supports the outcome of the experiments.
Experimental Section
General. General experimental details, suppliers, and experi-
mental procedures for the synthesis of novel compounds are
included in Supporting Information.
General Procedure for DKRs (Tables 1 and 2). To a glass
vial equipped with a stirring bar were added the substrate
(0.50 mmol), acyl donor 48 (0.21 mL, 1.5 mmol), Shvo catalyst
2 (0.027 g, 0.025 mmol), and N435 (10 mg) followed by toluene
(5.0 mL). After having been swept with argon, the vial was
closed, and the mixture was stirred while being heated in an
aluminum block kept at 80 °C. Analytical samples were taken at
every multiple of 24 h. The reaction was interrupted when the
conversion of the substrate was >50% as judged by HPLC
peak area comparison with an initial sample taken at 0 h, or after
120 h irrespective of the conversion at that time. The reaction
mixture was then diluted with 2-propanol to 50.0 mL. From
this mixture was decanted 1.00 mL, which was further diluted to
3.50 mL with 2-propanol in order to get an analytical sample
from which the reaction yield and the enantiomeric excess were
determined by chiral HPLC analysis, by comparison with
references. The remaining volume was filtered through Celite
before concentration in vacuo. The obtained residue was then
redissolved in dichloromethane. This solution was washed with
1.0 M NaOH and once with brine before drying (Na2SO4). The
residue obtained upon concentration in vacuo was purified by
silica gel flash chromatography using as eluent either a gradient
from n-hexane to n-hexane/dichloromethane:ethyl acetate, from
n-heptane to n-heptane/ethyl acetate, or from dichloromethane
to dichloromethane/methanol or a corresponding suitable iso-
cratic mixture.
FIGURE 7. The transition state of the substrate in entry 14. Two
hydrogen atoms migrate from the alcohol in a concerted way. Bond
˚
distances in A.
TABLE 3. Calculations on Relative Hydrogenation Energies
Table 1
entry
timea
(h)
conva
(%)
eea
(%)
ΔΕ*
(kcal)
entry
1
2
3
4
5
12
8
72
48
24
24
62
57
98
100
88
98
98
95
17.2
16.7
15.1
12.9
14
aFor reaction conditions, see Table 1.
The initial step of the mechanism involves coordination of
the alcohol to the Ru(0) complex for all four substrates. The
subsequent transition state for the formation of the corres-
ponding ketone is believed to be a concerted oxidative
transfer of two hydrogen atoms, one to the ruthenium
atom (resulting in the formation of a hydride) and the other
to the oxygen atom of the alcohol substrate (Figure 7).
This “outer-sphere” mechanism has been reported before.62b
In comparison to the conversions obtained experimentally,
an acceptable correlation with the respectively calculated
activation energies can be seen. For example, the substrate in
entry 4 has a calculated activation energy of 12.9 kcal/mol,
with a corresponding full conversion with 95% ee in the
DKR, in comparison to the substrate in entry 1, which has a
calculated activation energy of 17.2 kcal/mol and only 62%
conversion experimentally. Hence, as also can be seen in
entries 2 and 3, the trend of a low conversion in correlation to
a relatively high activation barrier is emerging. Although
(1R)-1-[5-Phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-
2-yl]ethyl acetate (R)-61 (entry 15, Table 1). The title compound
was obtained in 73% isolated yield as pale yellow oil after
purification on silica using isocratic mixture of heptane/EtOAc
(85/15, v/v). 1H NMR (CDCl3) δ 7.78-7.81 (m, 2H), 7.35-7.40
(m, 2H), 7.22-7.27 (m, 2H), 6.08 (q, J = 6.6 Hz, 1H), 5.53 (d,
J = 10.9 Hz, 1H), 5.24 (d, J = 10.9 Hz, 1H), 3.51-3.57 (m, 2H),
2.08 (s, 3H), 1.77 (d, J = 6.6 Hz, 3H), 0.91-0.95 (m, 2H), 0.01
(s, 9H); 13C NMR (CDCl3) δ 170.4, 146.8, 140.8, 133.8, 128.5,
126.9, 125.0, 116.0, 75.2, 66.4, 63.9, 21.2, 19.2, 17.8, -1.4.
HRMS calcd for C19H29N2O3Si (Mþ þ 1) 361.1947, found
361. [R]rtD (2.8 mg/mL, CHCl3) þ71.1
Synthesis of (1S)-1-[3-(4-Bromophenyl)-1,2,4-oxadiazol-
5-yl]ethanol (S)-13 (Scheme 3). L-(þ)-Lactic acid (2.83 g, 31.5
mmol), 12 (6.15 g, 28.6 mmol), and 1-hydroxybenzotriazole (386
mg, 2.86 mmol) was dissolved in DMSO (30 mL). While stirr-
ing at ambient temperature, N,N’-dicyclohexylcarbodiimide
(4.69 g, 37.2 mmol) was added dropwise. After stirring for 4 h,
J. Org. Chem. Vol. 74, No. 24, 2009 9335

Vallin et al.
JOCArticle
another portion of L-(þ)-lactic acid (773 mg, 8.6 mmol) and N,
N’-dicyclohexylcarbodiimide (3.6 g, 28.6 mmol) was added, and
the mixture was stirred for additional 3 h. Ethanol (200 mL)
was added, and the mixture was refluxed for 4 h. The ethanol
was removed by concentration in vacuo, and the result-
ing residue taken up in water (400 mL). The aqueous solu-
tion was extracted with dichloromethane. The organic phase
was dried (Na2SO4) and concentrated in vacuo. The obtained
crude product was purified by silica gel flash chromatography
(n-hexane/ethyl acetate 100:0 to 80:20) to yield analytically pure
title compound as a white solid (3.81 g, 50%) from the first
eluting product containing fractions. The fractions eluting right
thereafter contained less pure product, which was obtained as
a waxy solid (2.72 g, 35%). 1H NMR (DMSO-d6) δ 7.94 (d, J =
8.6 Hz, 2H), 7.77 (d, J = 8.6 Hz, 2H), 6.19 (d, J = 5.8 Hz, 1H),
5.06 (m, 1H), 1.54 (d, J = 6.6 Hz, 3H); 13C NMR (DMSO-d6)
δ 182.3, 166.8, 132.4, 129.0, 125.4, 125.2, 61.5, 21.3. HRMS
calcd for C10H10BrN2O2 (Mþ þ 1) 268.9926, found 268.9944.
[R]rtD (2.6 mg/mL, CHCl3) -3.8.
Preparation of (1S)-1-[5-(4-Bromophenyl)-1,2,4-oxadiazol-
3-yl]ethanol (S)-9 and (1R)-1-[5-(4-Bromophenyl)-1,2,4-oxadiazol-
3-yl]ethyl Acetate (R)-10 by KR of (rac)-1-[5-(4-Bromophenyl)-
1,2,4-oxadiazol-3-yl]ethanol (rac)-9. Isopropenyl acetate (3.60 g,
35.7 mmol), (rac)-9 (3.20 g, 11.89 mmol), and N435 (500 mg) were
stirred in toluene (200 mL) for 72 h at ambient temperature. The
mixture was then filtered and concentrated in vacuo to give a crude
product, which was separated by silica gel flash chromatography
(gradient from n-hexane to n-hexane/ethyl acetate 6:4). (R)-10
eluted as the first material and was obtained as a yellowish oil
(1.81 g, 49%), followed by (S)-9 that was obtained as a white
solid (1.58 g, 49%). (R)-10: 1H NMR (DMSO-d6) δ 8.04 (d, J =
8.4 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 5.98 (q, J = 6.6 Hz,
1H), 2.10 (s, 3H), 1.61 (d, J = 6.6 Hz, 3H); 13C NMR (DMSO-d6)
δ 174.8, 170.4, 169.5, 132.7, 129.8, 127.4, 122.3, 63.8, 20.6,
18.5; Anal. Calcd for C12H11BrN2O3: C, 46.3; H, 3.6; N, 9.0.
Found: C, 46.4; H, 3.7; N, 9.3. [R]rtD (2.5 mg/mL, CHCl3): þ101.1.
(S)-9: The 1H NMR spectrum was identical to that obtained
for (rac)-9. Anal. Calcd for C10H9BrN2O2: C, 44.6; H, 3.4;
N, 10.4. Found: C, 44.5; H, 3.5; N, 10.3. [R]rt (2.6 mg/mL,
D
CHCl3) -123.1.
9
Acknowledgment. We gratefully acknowledge the Ruder
Boskovic Institute, Zagreb and AstraZeneca R&D,
ꢀ
ꢁ
€
€
Sodertalje for providing laboratory facilities to Dr. David
Wensbo Posaric and Dr. Karl Vallin, respectively. Financial
ꢁ
support to Dr. Karl Vallin from the Carl Trygger foundation
is gratefully acknowledged. We also thank Prof. Tobias Rein
and Dr. Gabor Csjernyik for proofreading this manuscript, as
€
well as Prof. Jan-E. Backvall and Adj. Prof. Jan E. Nystrom
for creative discussions.
€
Supporting Information Available: Synthesis and analysis
data for all substrates, (D)KR experimental conditions, as
well as Cartesian coordinates of calculated complexes. This
material is available free of charge via the Internet at http://
pubs.acs.org.
9336 J. Org. Chem. Vol. 74, No. 24, 2009