Synthesis of enantiopure 3,6,7,8-tetrahydrochromeno[7,8-d]imidazoles via asymmetric ketone hydrogenation in the presence of RuCl2[Xyl-P-Phos][DAIPEN]

Article abstract of DOI:10.1016/j.tetasy.2008.08.022

The asymmetric hydrogenation of complex heterocyclic ketones 1 in the presence of the novel catalyst RuCl₂[(S)-Xyl-P-Phos][(S)-DAIPEN] and a base afforded the corresponding alcohols 2 in good enantiomeric purity. The outcome of the reaction dep

Full text of DOI:10.1016/j.tetasy.2008.08.022

Tetrahedron: Asymmetry 19 (2008) 2102–2110
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of enantiopure 3,6,7,8-tetrahydrochromeno[7,8-d]imidazoles
via asymmetric ketone hydrogenation in the presence
of RuCl2[Xyl-P-Phos][DAIPEN]
a
a
b
Andreas Marc Palmer a, , Vittoria Chiesa , Hans Christof Holst , Jacques Le Paih ,
*
Antonio Zanotti-Gerosa b, , Ulrike Nettekoven
c
*
a NYCOMED GmbH, Departments of Medicinal Chemistry and Physicochemistry, Byk-Gulden-Str. 2, D-78467 Konstanz, Germany
b Johnson Matthey, Catalysis and Chiral Technologies, 28 Cambridge Science Park, Milton Road, Cambridge CB4 0FP, United Kingdom
c Solvias AG, Department of Synthesis and Catalysis, Mattenstraße 22, CH-4002 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 August 2008
Accepted 21 August 2008
The asymmetric hydrogenation of complex heterocyclic ketones 1 in the presence of the novel catalyst
RuCl2[(S)-Xyl-P-Phos][(S)-DAIPEN] and a base afforded the corresponding alcohols 2 in good enantio-
meric purity. The outcome of the reaction depended on the substitution pattern of the ketone and the
stoichiometry of the base. After optimization of the reaction conditions, the pure alcohols 2a and 2b were
isolated in good yield (>70%) and enantiomeric purity (>93% ee) and used as key intermediates for the
synthesis of the pharmaceutically active 3,6,7,8-tetrahydrochromeno[7,8-d]imidazoles 3a and 3b.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
The synthesis of the compounds of class 3 in enantiomerically
enriched or enantiopure form was designed around the two key
Acid related diseases, such as gastroesophageal reflux disease
(GERD), have a high prevalence and influence strongly the quality
of life of the affected patients.1 The reversible inhibition of the gas-
tric proton pump enzyme (H+/K+-ATPase) represents an important
approach in the development of drugs against these medical condi-
tions. Over the past two decades, one important approach for the
identification of potent potassium-competitive acid blockers
(P-CABs) relied on the structural class of substituted imidazo[1,2-
a]pyridines. Recently, we described the discovery and the enantio-
selective synthesis of tricyclic imidazo[1,2-a]pyridines, such as, for
example, BYK 311319 6 (R0 = R00 = Me, Ar = Ph) which are highly po-
tent reversible inhibitors of the H+/K+-ATPase, and possess promis-
ing pharmaceutical properties.2 Nevertheless, our work in the field
of imidazo[1,2-a]pyrazines and pyrrolo[3,2-b]pyridines demon-
strated that the imidazo[1,2-a]pyridine scaffold does not consti-
tute an indispensable structural element of potent P-CABs.3
Herein, we report the synthesis of enantiopure 3,6,7,8-tetrahydro-
chromeno[7,8-d]imidazoles of the general formula 3, which are
isomers of the 7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-a]pyri-
dines of the general formula 6. The biochemical and pharmacolog-
ical properties of these derivatives will be reported in due course.
steps of asymmetric hydrogenation of ketones 1 and subsequent
Mitsunobu cyclization of the resulting diols 2 (Scheme 1). A similar
approach had already proven its value in the preparation of the
related class of imidazopyridines 6, via the reduction of precursor
4 and cyclization of 5.2,4 The ketones of the general formula 1 were
prepared in an analogous manner to imidazopyridine ketones of
the general formula 4.2,5
The introduction, in the mid 90s, of catalysts of the type
RuCl2[PP][NN] ([PP] = chiral diphosphine, [NN] = chiral 1,2-di-
amine) represented a breakthrough in the field of the asymmetric
catalytic reduction of aryl ketones.6 Very high enantioselectivities
and activities were obtained on a wide range of ketones, particu-
larly when catalyst RuCl2[Xyl-BINAP][DAIPEN]
8 was used
(Fig. 1). A number of applications to industrially relevant molecules
have been reported, including the asymmetric reduction of com-
plex heterocyclic ketones.7 As part of the research on a scalable
efficient route to products 6, we developed the catalyst RuCl2[(S)-
Xyl-P-Phos][(S)-DAIPEN], 9 (Fig. 1),4,8 and successfully applied it
to the asymmetric hydrogenation of ketones 4, achieving high
enantioselectivity (>95% ee) and high activity (up to a molar sub-
strate to catalyst ratio, S/C, of 5000:1). The complex nature of the
substrates required the development of new reaction conditions.
While the asymmetric hydrogenation of aryl ketones is generally
carried out in the presence of substoichiometric amounts of base
(i.e., t-BuOK in 2-PrOH), in the case of substrates 4, concern about
the presence of the mildly acidic phenol group was overcome by
* Corresponding authors. Tel.: +49 7531 844783; fax: +49 7531 8492087 (A.M.P.);
tel.: +44 1223 225809; fax: +44 1223 438037 (A.Z.-G.).
E-mail addresses: andreas.palmer@nycomed.com (A. M. Palmer), antonio.zanotti-
gerosa@matthey.com (A. Zanotti-Gerosa).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.08.022

A. M. Palmer et al. / Tetrahedron: Asymmetry 19 (2008) 2102–2110
2103
approach.9 Over the course of such an experiment, 96 different
hydrogenation reactions were assembled in glass vials under an in-
ert atmosphere by a dispensing robot. The vials were placed on a
metal plate in a reactor block. The block was set under hydrogen
pressure and heated and shaken continuously to enable hydroge-
nation of the 96 reactions at identical pressure (80 bar) and tem-
perature (80 °C). The substrate to catalyst ratio (S/C ratio)
employed was 25. The reactions were stopped after 24 h of reac-
tion time and subjected to supercritical fluid chromatography for
analysis. In detail, 19 ligands of various ligand classes (Taniaphos,
Josiphos, Walphos, Mandyphos, MeOBIPHEP, Naud oxazolines)
were investigated.10 Ligands belonging to the BINAP family were
also included. Six different metal precursors were used for the
in situ formation of the respective hydrogenation catalyst:
[Rh(nbd)Cl]2, [Rh(nbd)2]BF4, [RuCl2(p-cymene)]2, [Ru(cod)-
(OTFA)2], [RuCl2(PPh3)3], [Ir(cod)Cl]2 and [Ir(cod)2]BF4. Addition-
ally, six different ruthenium precatalysts were employed. Six
solvents (dichloromethane, methanol, 1,2-dichloroethane, toluene,
2-propanol, water) and five additives (triethylamine, tetrafluorob-
oric acid dimethyl ether complex, potassium tert-butylate, sodium
hydroxide, potassium carbonate) were used over the course of the
HTS screening. For the majority of the reactions, little to no conver-
sion was observed. Only rhodium catalysts gave significant conver-
sion and product formation. Neither the tested Noyori Ru-PP–NN
systems nor the Naud catalysts gave conversions >50%. The ob-
served ee values were rather low. In Table 1, the results of single
experiments performed in a 50 ml autoclave are summarized.
Catalyst 7 and ligand 10, which had performed successfully on re-
lated substrates, and ligand 11 that constituted the most promising
ligand identified in the course of the HTS screening, were used for
these experiments.
O
O
R'
O
R'
N
N
N
N
N
N
(a)
R''
R''
OH
HO
OH
1
2
Ar
Ar
1a-6a
: R', R'' = Me, Ar = C6H5
(b)
1b-6b
: R', R'' = Me, Ar = 2-MeC6H4
O
O
R'
R'
N
N
N
R''
N
N
R''
N
O
O
Ar
6
Ar
3
(b)
O
O
R'
R'
N
N
N
N
(a)
N
R''
R''
N
HO
OH
O
OH
The enzymatic reduction of ketone 1b to the corresponding
(R)-configured alcohol 2b was also investigated applying various
alcohol dehydogenases (ADHs) and ADH variants derived from
Lactobacillus brevis, Thermoanerobacter, Rhodococcus, Candida
parapsilosis, Lactobacillus kefir and Thermoanerobium brokii.11
However, none of the enzymes tested exhibited the potential to
carry out the desired reduction.
Ar
Ar
5
4
Scheme 1. Synthesis of enantiopure 3,6,7,8-tetrahydrochromeno[7,8-d]imidazoles
3 and 7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-a]pyridines 6.
using 1 equiv of base to deprotonate the hydroxy function and a
small excess of base to activate the catalyst. It was also found that
the addition of a small amount of water (10–20%) had a beneficial
effect on the conversion at lower catalyst loadings. Using a larger
excess of base increased the reaction rates and no by-products
were detected over the course of the reaction.
2.2. Successful asymmetric reduction of ketones 1a and 1b
using RuCl2[(S)-Xyl-P-Phos][(S)-DAIPEN]
Since no promising hydrogenation catalysts suitable for the effi-
cient and enantioselective transformation of ketones 1 into alco-
hols 2 were identified in the course of the HTS screening, we
focused on the complex RuCl2[(S)-Xyl-P-Phos][(S)-DAIPEN] 9. As
mentioned above, this catalyst has already proven its value in
the transformation of the structurally related ketones 4.4 We first
studied the hydrogenation of the ‘parent’ compound 1a (Ar = Ph
and R0 = R00 = Me) and used a procedure that was broadly based
2. Results and discussion
2.1. Identification of a suitable method for the asymmetric
reduction of ketone 1b
The asymmetric reduction of ketone 1b (Ar = 2-methylphenyl
and R0 = R00 = Me) was studied in a detailed manner using a HTS
Ph
P
OMe
OMe
OMe
Ph
N
Ar Ar H H
Cl
Ar
Cl
Ru
Cl
Ar
Ar
Ar
H H
N
O
OMe
OMe
P
P
N
N
P
P
N
OMe
OMe
Ru
Cl
N
N
P
P
Ar
Ar
H H
H H
Fe
Fe
N
Ph Ph
Ph Ph
OMe
7
(Ar = Ph)
8
(Ar = 3,5-dimethylphenyl)
10
11
9 (Ar = 3,5-dimethylphenyl)
Figure 1. Structure of the catalysts RuCl2[(S)-BINAP][(S)-DAIPEN], 7, RuCl2[(S)-Xyl-BINAP][(S)-DAIPEN], 8, RuCl2[(S)-Xyl-P-Phos][(S)-DAIPEN], 9, and the ligands Naud
oxazoline N003-1, 10, Taniaphos T001-1, 11.

2104
A. M. Palmer et al. / Tetrahedron: Asymmetry 19 (2008) 2102–2110
Table 1
Asymmetric catalytic hydrogenation of ketone 1b (S/C = 100:1, t = 16–20 h, c = 0.1 M)
Entry
Metal
Ligand
Solvent
Additive
pH2 (bar)
T (°C)
Conv.a (%)
% ee
1
2
3
4
5
6
Rh(nbd)2BF4
Rh(nbd)2BF4
Rh(nbd)2BF4
[RuCl2(p-cymene)]2
11
11
11
11
MeOH/CH2Cl2
MeOH
MeOH
—
—
—
80
80
80
60
60
60
80
80
50
80
80
80
100
100
60
<5
<5
13
15
16
n.d.
n.d.
n.d.
MeOH
Et3N
K2CO3
t-BuOK
[RuCl2(PPh3)(10)]
2-PrOH/TFEb
2-PrOH
RuCl2[(S)-BINAP][(S)-DAIPEN]c
<10
a
Conversion determined by HPLC.
TFE = trifluoroethanol.
Catalyst 7 (depicted in Fig. 1).
b
c
Table 2
Asymmetric catalytic hydrogenation of ketone 1a
Entry
Cat.
S/C
Basea
Solventb
2-PrOH
T (°C)
Conv.c (%)
1
2
3
4
5
6
7
8
9
9
9
9
9
9
9
9
9
9
8
8
500:1
500:1
500:1
1000:1
1000:1
1000:1
1000:1
1000:1
1000:1
250:1
1.2 equiv t-BuOK
1.2 equiv t-BuOK
25% aq KOH
1.2 equiv t-BuOK
1.5 equiv t-BuOK
1.2 equiv t-BuOK
1.2 equiv t-BuOK
10% aq KOH
70
70
70
70
70
75
75
70
70
70
70
100
100
100
62–94
86
79
51
89
92
2-PrOH/10% H2O
50% t-BuOH/25% 2-PrOH
2-PrOH/10% H2O
2-PrOH/10% H2O
2-PrOH/10% H2O
2-PrOH/20% H2O
40% t-BuOH/50% 2-PrOH
50% t-BuOH/25% 2-PrOH
2-PrOH
25% aq KOH
1.2 equiv t-BuOK
1.2 equiv t-BuOK
10
11
100
65
500:1
2-PrOH
a
1 M solution of t-BuOK in t-BuOH or 10 M aq KOH solution.
b
c
Reactions were run in a Biotage Endeavour: 25 bar H2, 16 h, substrate concentration of 0.25 M (entries 1–3, 10 and 11) or 0.33 M (entries 4–9).
Conversion determined by HPLC and/or 1H NMR.
on the protocol followed for the reduction of imidazo[1,2-a]pyri-
dines 4 (Table 2, Scheme 1). In the presence of catalyst RuCl2[(S)-
Xyl-P-Phos][(S)-DAIPEN], 9, and 1.2 equiv of base, the reduction
proceeded smoothly overnight at S/C 500:1, with anhydrous sol-
vents (Table 2, entry 1) as well as with wet solvents (entry 2). Since
it can be expected that the addition of water to potassium tert-
butylate causes the formation of potassium hydroxide, it was also
proven that the use of excess aqueous potassium hydroxide was
effective for producing the desired reaction (entry 3). Under the same
reaction conditions at S/C 1000:1 the reaction proceeded in a less reli-
able manner (entry 4, 62–94% conversion). Whereas a slight increase
of the base stoichiometry (entry 5) or reaction temperature (entry 6)
appeared to be beneficial, a decrease in conversion was observed in
the presence of higher amounts of water (entry 7). Again, in the
presence of excess aqueous potassium hydroxide, the reaction ap-
proached full conversion (entries 8 and 9). At S/C 500:1, RuCl2[(S)-
strates 1 and the use of neat organic solvents was preferred for fur-
ther development.
Compound 3b (Ar = 2-methylphenyl, R0 = R00 = Me) was consid-
ered the most interesting member of the class and the hydrogena-
tion of 1b was studied on a larger scale. High enantioselectivity
was first demonstrated on small scale under the conditions already
tested for 1a (Table 3), although at reduced catalyst loadings due to
the reduced reactivity of the substrate which, in turn, can be attrib-
uted to its increased steric bulk. At S/C 250:1 some erosion of
enantioselectivity took place when a higher amount of base was
used (Table 3, entry 3).
Table 3
Asymmetric catalytic hydrogenation of ketone 1b
Entry
Cat.
S/C
Basea,b
Conv.c (%)
eed (%)
Xyl-BINAP][(S)-DAIPEN]
8 was found to be less active than
1
2
3
9
9
9
100:1
250:1
250:1
2.7 equiv t-BuOK
1.7 equiv t-BuOK
2.7 equiv t-BuOK,
100
100
100
92–95
95
89–92
RuCl2[(S)-Xyl-P-Phos][(S)-DAIPEN], 9, (entry 11 vs entry 1) and, in
order to achieve full conversion, the catalyst loading was increased
to S/C 250:1 (entry 10). Since at the time a suitable analytical method
was not available, the preliminary experiments of Table 2 could not
be analyzed for enantioselectivity. The enantioselectivity was later
determined by capillary electrophoresis (CE) on isolated samples of
2a and was found to be consistently very high (>97% ee) when the
catalyst RuCl2[(S)-Xyl-P-Phos][(S)-DAIPEN] 9 had been used. On the
other hand, an isolated sample of product 2a obtained from
RuCl2[(S)-Xyl-BINAP][(S)-DAIPEN] 8 (entry 10) showed surprisingly
low enantiomeric purity (25% ee). The asymmetric reduction of ke-
tone 1a was then performed on a 2 g scale (S/C = 310:1, 1.45 equiv
of t-BuOK, 80 bar H2, 65 °C, 23 h) and diol 2a was isolated in 70% yield
and 98% ee.
a
Reactions were run in a Biotage Endeavour: 2-PrOH, 30 bar H2, 65 °C, 16 h,
substrate concentration of 0.18 M.
b
1 M solution of t-BuOK in t-BuOH.
Conversion determined by HPLC and/or 1H NMR.
c
d
Ee determined by HPLC.
The hydrogenation of substrate 1b was then reproduced in
100 ml to 2 l autoclaves (Scheme 1). On a 35 g scale using an S/C
ratio of 100:1, the transformation proceeded smoothly in the pres-
ence of 1.1 equiv of t-BuOK (2-PrOH, 80 bar H2, 70 °C, 20 h) and the
diol 2b was isolated in good yield (76%) and enantiomeric purity
(93.8% ee). However, when the hydrogenation was conducted at
an S/C ratio of 250:1 and the amount of base was increased to
1.7 equiv under otherwise identical reaction conditions, the
desired product 2b was formed in mixture with a by-product,
which could be isolated by chromatography, it was fully character-
In general it was found that benzimidazole ketone 1a was less
reactive than the corresponding imidazo[1,2-a]pyridine 4a (Ar = Ph
and R0 = R00 = Me). Furthermore, it was thought that the presence of
water would further reduce the already limited solubility of sub-

A. M. Palmer et al. / Tetrahedron: Asymmetry 19 (2008) 2102–2110
2105
Table 4
H
O
O
Asymmetric catalytic hydrogenation of ketones 1c–1s
O
O
N
N
N
N
R
R
N
N
N
N
Table 4
OH
12b (enol form)
OH
12b (diketo form)
HO
OH
HO
OH
1c-s
2c-s
Ar
Ar
m, o, p, r, s:
Figure 2. Structure of by-product 12b formed during catalytic asymmetric hydro-
genation of ketone 1b.
c-l: R = C(O)NMe2
Ar = 2-Me-phenyl
c: Ar = 2-F-phenyl
d: Ar = 4-F-phenyl
e: Ar = 2-Cl-phenyl
f: Ar = 2-CF3-phenyl
g: 2-Et-phenyl
h: 2-Me-4-F-phenyl
i: 2-(MeOCH2)-phenyl
j: 2-(BnOCH2)-phenyl
k: thiophen-2-yl
l: 2-Me-thiophen-3-yl
m: R = C(O)pyrrolidine
o: R = C(O)azetidine
p: R = C(O)NH(c-Pr)
r: R = C(O)NHMe
ized and identified as compound 12b (Fig. 2). Compound 12b was
presumably caused by formation of a reactive enolate that then
attacked the amido group. An analogous by-product has never
been detected in the imidazopyridine class. The absence of such
a side reaction in the latter class of substrates may be attributed
to the different electronic nature of the heterocyclic scaffold (thus
producing a different activation of the carboxamide group towards
nucleophilic attack) or to the higher reactivity of imidazopyridine
ketones, 4 (thus disfavouring the competitive cyclization side
reaction). Although the use of high base concentrations is generally
expected to increase the reaction rate, the formation of side prod-
ucts of type 12 discouraged the use of a large excess of base for the
hydrogenation of ketones 1, above the 1 equiv required for neutral-
ization of the phenol moiety.
s: R = CH2OMe
n, q: Ar = phenyl
n: R = C(O)azetidine
q: R = C(O)NHMe
Entry
SM
S/C
Basea (equiv)
Conditionsb
Yield/eec (%)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
300:1
500:1
100:1
100:1
100:1
100:1
100:1
100:1
100:1
100:1
100:1
430:1
100:1
100:1
500:1
100:1
100:1
1.5
1.1
2.7
2.0
Ad
Ad
B
C
B
B
C
C
C
2c: 49/96e
2d: 35/88
2e: 48/88
2f: 16/72
2g: 51/86
2h: 61/83
2i: 66/97
2j: 64/96
2k: 62/80
2l: 63/96
2m: 94/91
2n: 32/85
2o: 10/95
2p: 45/98
2q: 52/77
2r: 30/95
2s: 71/98
12e: 26
12f: 31
12g: 32
12h: 17
2.75
2.75
1.1
1.1
1.5
1.1
2.7
1.2
ꢀ6
2.3. Application of the hydrogenation method on structurally
related ketones 1c–1s
C
1m
1n
1o
1p
1q
1r
1s
C
The interest in the class of compounds 3 prompted us to expand
upon the scope of the substrates under examination (Table 4). Dif-
ferent substitution patterns at the aryl moiety and at the amido
group were explored and it was found that the results of the asym-
metric hydrogenation step varied to a surprisingly large degree.
The effect of different aryl groups was explored first, while keeping
the dimethylamido group fixed (Table 4, entries 1–10). The reduc-
tion of the isomeric fluorophenyl-substituted ketones 1c and 1d
was conducted at high S/C ratios and in the presence of water.
Although quantitative conversion occurred in the presence of
1.1–1.5 equiv of base, the corresponding alcohols 2c and 2d were
isolated in rather low yield (entries 1 and 2). The presence of an
ortho-substituent on the aromatic ring of the ketones 1 generally
gave high selectivity but at, the same time, a diminished activity
towards reduction. Consequently, when the hydrogenation was
performed in the presence of 2.0–2.75 equiv of base, significant
amounts of by-products 12 were formed, which were isolated by
chromatography (17–32% yield) and their structure confirmed by
NMR spectroscopy (entries 3–6). The corresponding alcohols 2e–
2h were obtained with an enantiomeric purity of 72–88% ee. On
the other hand, when the hydrogenation was conducted in the
presence of only 1.1 equiv of base, the alcohols were obtained with
better enantiomeric purity and no by-product 12 was isolated
(entries 7 and 8).
Ad
C
12b: 69
2.75
1.2
6.25
1.4
C
Ad
C
A
a
Base: 10 M aq solution of KOH (entries 13, 16), 1 M solution of t-BuOK in t-
BuOH (all other entries).
b
Conditions: A: 100 ml Premex Hastelloy autoclave, 80 bar H2; B: 25 ml Parr
microreactor, 25 bar H2; C: 8 ꢁ 10 ml Biotage Endeavour, 25 bar H2; A–C: 2-PrOH/t-
BuOH, 65–80 °C, 16–20 h.
c
Ee measured by HPLC or capillary electrophoresis.
Hydrogenation in the presence of 4–10% of H2O.
Enantiomeric purity was determined after Mitsunobu cyclization.
d
e
brought a significant amount of by-products. Only the use of a
large excess of base gave conversion but afforded almost exclu-
sively a mixture of by-products (including 12b). The very low sol-
ubility of some substrates also played a role, for example, in the
case of the N-monosubstituted amides 1p and 1r (entries 14 and
16). The comparison of the results obtained for the reduction of
ketones 1n/1o (entries 12 and 13) and 1q/1r (entries 15 and 16)
is of special interest: the asymmetric reduction of 1n and 1q,
which possess a phenyl residue instead of a 2-methylphenyl sub-
stituent, was feasible even at high S/C ratios of 430–500:1 and
afforded the alcohols 2n and 2q in 32% and 52% yield, respectively.
On the other hand, the enantioselectivity was compromised under
these conditions (77–85% ee as compared to 95% ee). Ketone 1s,
which possesses a methyloxymethylene residue rather than a car-
boxamide group, reacted smoothly in the presence of 1.4 equiv of
base and the corresponding chiral alcohol 2s was obtained in
71% yield and 98% ee (entry 17).
Furthermore, no by-products 12 were isolated over the course
of the reduction of the thiophene ketones 1k–1l (entries 9 and
10). Interestingly, the thiophen-2-yl-substituted alcohol 2k was
obtained in an enantiomeric purity of 80% ee (entry 9), whereas
the structurally related 2-methyl-thiophen-3-yl-substituted alco-
hol 2l was obtained in a much higher enantiomeric purity of 96%
ee (entry 10).
Surprisingly, a high chemoselectivity was obtained when the
pyrrolidinamido group was present instead of the dimethylamido
group (entry 11). Substrates containing other amido substituents
(entries 13, 14 and 16) gave different results, possibly reflecting
the different levels of activation towards nucleophilic attack from
the ketone enolate. The presence of the azetidine ring (entry 13)
2.4. Transformation of chiral diols into target compounds 3
The transformation of alcohols 2 to target compounds 3 was
achieved under standard conditions that had previously been
developed for the imidazopyridine class (Scheme 1):2,5 when a

2106
A. M. Palmer et al. / Tetrahedron: Asymmetry 19 (2008) 2102–2110
mixture of alcohol 2, triphenylphosphine and DIAD in THF was stir-
red at room temperature, the corresponding 3,6,7,8-tetrahydro-
or a 100 ml Premex Hastelloy autoclave using either t-BuOK (1 M
in t-BuOH) or KOH (10 M in H2O) as base and mixtures of
t-BuOH/2-PrOH as solvent. In some cases, water was added (see
Table 4). In all cases, >95% conversion of substrate 1 was obtained.
The crude products 2c–2s were isolated by work up with aqueous
NH4Cl solution/CH2Cl2 and, except for product 2r (44% mass recov-
ery), 74–100% mass recovery was obtained. The crude products
were purified by column chromatography (silica gel, eluant:
CH2Cl2/MeOH) and—in some cases—by an additional crystalliza-
tion step. The reactions were conducted in analogy to the
detailed experimental procedures given for the synthesis of diols
2a and 2b.
chromeno[7,8-d]imidazole
3 typically was formed over the
course of several minutes. The cyclization always took place with
high stereoselectivity and, within the limit of experimental error,
the enantiopurity of the final products 3 reflected the enantiopuri-
ty of the alcohols 2, for example, target compounds 3a and 3b were
obtained in 77% yield (95.8% ee)/84% yield (95.6% ee).
3. Conclusion
In conclusion, we have reported a three-step synthesis of enan-
tiomerically enriched 3,6,7,8-tetrahydrochromeno[7,8-d]imida-
zoles 3 comprising the preparation of prochiral ketones 1, the
asymmetric hydrogenation of these substrates and the Mitsunobu
cyclization of the obtained diols 2. For the asymmetric hydrogena-
tion step, a variety of catalysts were screened using a HTS method.
However, the novel Noyori type complex RuCl2[(S)-Xyl-P-
Phos][(S)-DAIPEN] 9 was the only catalyst suitable for the effective
transformation of ketones 1 affording alcohols 2 in moderate to
good yields and excellent enantiomeric purity. The outcome of
the asymmetric reduction and the rate of the competing base-cat-
alyzed reaction leading to by-products 12 depended on the substi-
tution pattern of the respective ketone 1. After optimization of the
reaction conditions, target compounds 3a and 3b were obtained in
good yield. Nevertheless, the therapeutic significance of 3,6,7,8-
tetrahydrochromeno[7,8-d]imidazoles 3 makes the development
of a cost-effective process an on-going effort.
4.3. Determination of the enantiomeric purity of alcohols by
capillary electrophoresis 2b, 2d–2i, 2l–2r
The separation of enantiomers by CE was performed using the
following experimental set-up (tM = migration time): Capillary:
56/64.5 cm ꢁ 50
lm barefused silica bubble (Agilent). Buffer:
50 mM sodium phosphate, pH 2.5. Chiral selector: 40 mM hepta-
kis(2,3,6-tri-O-methyl)-b-cyclodextrin. Voltage: 30 kV. Tempera-
ture: 20 °C (except for 2e), 10 °C (2e). Detection: Diode array
219/226 nm.
4.4. Determination of the enantiomeric purity of alcohols by
HPLC 2j–2k, 2s
The separation of enantiomers by HPLC was performed using
the following experimental set-up (tR = retention time): column:
Daicel Chiralpak AD-H, 250 ꢁ 4.6 mm, 5
lm, flow rate: 1 ml/min,
diode array detection at 218 nm, eluant: see corresponding
4. Experimental
4.1. General
experiment.
4.5. Analysis of the crude products (conversion, enantiomeric
excess) by HPLC (2e–2i, 2l–2m, 2o–2p, 2r), ‘HPLC analytical
method’
All chemicals were purchased from the major chemical suppliers
as highest purity grade and used without any further purification.
The progress of the reaction was monitored on Macherey-Nagel
HPTLC plates Nano-SIL 20 UV254 (0.20 mm layer, nano Silica Gel
60 with fluorescence indicator UV254) using CH2Cl2/MeOH as sol-
vent system. Column chromatography was performed with Merck
Silica Gel 60 (70–230 mesh ASTM) with the solvent mixtures spec-
ified in the corresponding experiment. Spots were visualized by
iodine vapour or by irradiation with ultraviolet light (254 nm).
Melting points (mp) were taken in open capillaries on a Büchi B-
540 melting point apparatus and are uncorrected. 1H NMR spectra
were recorded with a Bruker DRX 200 FT-NMR spectrometer at a
frequency of 200 MHz, a Bruker AV 300 FT-NMR spectrometer at
a frequency of 300 MHz, or a Bruker AV 400 FT-NMR spectrometer
at a frequency of 400 MHz. 13C NMR spectra were acquired with a
Bruker AV 400 FT-NMR spectrometer at a frequency of 100 MHz.
DMSO-d6 was used as solvent. The chemical shifts are reported as
parts per million (d ppm) with tetramethylsilane (TMS) or DMSO
The analysis of the crude products by HPLC was performed with
a Merck LichroCART 250-4, Chiradex (5 lg) column applying the
conditions specified in the corresponding experiment. For all other
alcohols 2, the conversion was judged from the 1H NMR-spectrum
of the crude product, and the enantiomeric excess was determined
by the reported CE/HPLC-method.
4.6. 4-Hydroxy-5-[(3R)-3-hydroxy-3-phenylpropyl]-N,N,1,2-
tetramethyl-1H-benzimidazole-6-carboxamide 2a
In a flask filled with argon, ketone 1a (2.0 g, 5.5 mmol) was
suspended in 2-PrOH (2.8 ml) and H2O (4.1 ml). t-BuOK (1 M in
t-BuOH, 8.0 ml), t-BuOH (20 ml) and 9 (22 mg, 0.017 mmol, S/C
310:1) were added and the mixture was transferred into a
100 ml Premex Hastelloy autoclave and hydrogenated for 23 h at
65 °C and 80 bar H2-pressure. After cooling to rt and releasing of
the H2-pressure, the reaction mixture was concentrated in vacuo.
The residue was purified by column chromatography [SiO2, eluant:
CH2Cl2/MeOH = 14:1 (v/v)]. Two batches of the title compound
were obtained, which were crystallized from acetone: Batch 1:
0.5 g of a beige solid (25% yield, mp 261–263 °C), batch 2: 0.9 g
of a beige solid (45% yield, 97.4% ee, mp 263–265 °C). Determina-
tion of the enantiomeric purity by CE (capillary: Agilent bubble-
as the internal standard (1H: dTMS
= =
0.00 ppm; 13C dDMSO
39.50 ppm). High resolution mass spectra were obtained on a Bru-
ker Daltonics MicroTOF Focus instrument using electrospray ioni-
zation (ESI positive). Elemental analysis was performed on a Carlo
Erba 1106 C, H, N analyzer. The enantiomeric purity of the target
compounds and of selected intermediates was determined by cap-
illary electrophoresis (CE, see Section 4.3) and/or high pressure
liquid chromatography (HPLC, see Section 4.4).
cell 64.5 cm ꢁ 75
lm; buffer: 50 mM sodium phosphate, pH 2.5;
4.2. General procedure for the asymmetric hydrogenation of
ketones 1c–1s
chiral selector: 40 mM heptakis(2,3,6-tri-O-methyl)-b-cyclodex-
trin; 30 kV; 10 °C): tM [(3S)] = 16.1 min/1.3 area %; tM [(3R)] =
16.4 min/98.7 area %; 97.4% ee. 1H NMR (DMSO-d6, 400 MHz):
d = 1.73 (br s, 1H, 20-Ha), 1.91 (br s, 1H, 20-Hb), 2.20–2.85 (m, 2H,
10-Ha, 10-Hb), 2.49 (s, 3H, 2-CH3), 2.68 (s, 3H, N(CH3)2), 2.89 (s,
The hydrogenation reactions were conducted at 65–80 °C in a
8 ꢁ 10 ml Biotage Endeavour apparatus, a 25 ml Parr microreactor

A. M. Palmer et al. / Tetrahedron: Asymmetry 19 (2008) 2102–2110
2107
3H, N(CH3)2), 3.64 (s, 3H, 3-CH3), 4.48 (br t, 1H, 30-H), 5.13 (br s, 1H,
OH), 6.70 (s, 1H, 4-H), 7.21 (mc, 1H, Ph), 7.30 (mc, 4H, Ph), 9.87 (br
s, 1H, OH). 13C NMR (DMSO-d6, 100 MHz): d = 13.1 (2-CH3), 23.4
(C-10), 29.7 (3-CH3), 33.8, 38.3 (CON(CH3)2), 72.6 (C-30), 97.6 (C-
4), 125.9, 126.4, 127.8 (Ph), 116.1, 131.3, 132.0, 135.0, 145.7,
146.0, 150.8 (4 °C), 170.7 (CON(CH3)2), overlay of C-20 signal with
4.10. 5-[(3R)-3-(2-Chlorophenyl)-3-hydroxypropyl]-4-hydroxy-
N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide 2e
Preparation according to Section 4.2: foamy solid. HPLC
analytical method (see Section 4.5): eluant: methanol/water =
25/75, 1 ml/min, tR (enantiomer 1) = 19.2 min, tR (enantiomer
2) = 24.8 min, tR (1e) = 27.6 min. Determination of the enantio-
meric purity by CE (see Section 4.3): tM [(3S)] = 21.9 min/5.8
area %; tM [(3R)] = 23.7 min/94.2 area %; 88.4% ee. 1H NMR
(DMSO-d6, 400 MHz): d = 1.69 (br s, 1H), 1.81 (br s, 1H), 2.38,
2.50 (br s, s), 2.69, 2.70 (s, br s, 4H), 2.89 (s, 3H), 3.64 (s, 3H),
4.89 (br s, 1H), 5.34 (br s, 1H), 6.70 (s, 1H), 7.24 (mc, 1H), 7.35
(mc, 2H), 7.58 (d, 1H), 9.78 (br s, 1H).
DMSO signals. HRMS (ESI) m/z
368.1969, found: 368.1954.
C
21H26N3O3 [M+H]+ calcd:
4.7. 4-Hydroxy-5-[(3R)-3-hydroxy-3-(2-methylphenyl)-propyl]-
N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide 2b
In a flask filled with argon, ketone 1b (35.0 g, 92 mmol) was
suspended in degassed 2-PrOH (340 ml) and t-BuOK solution
(1 M in t-BuOH, 101 ml) was slowly added. The yellow suspension
was stirred at rt until a solution was obtained (20 min). Catalyst 9
(1.14 g, 0.92 mmol, S/C 100:1) was added and stirring was contin-
ued for several min. The brown solution was transferred into a 2 l
autoclave with glass inlay, purged with H2 (3ꢁ) and hydrogenated
at 70 °C and 80 bar pressure for 20 h. After cooling to rt and releas-
ing of the H2-pressure, the reaction mixture was poured into a stir-
red mixture of satd NH4Cl solution (400 ml) and CH2Cl2 (700 ml).
The phases were separated and the aq phase extracted with CH2Cl2
(2 ꢁ 80 ml). The combined organic phases were washed with
water (400 ml), dried over Na2SO4 and concentrated under reduced
pressure. The residue (41 g of a green foam, 94.9% ee) was dis-
solved in hot acetone (100 ml). Upon cooling to rt, crystallization
started. After a period of 3 h at rt and 2 h at 0 °C, the precipitate
was isolated by filtration, washed with acetone (20 ml) and Et2O
(40 ml) and dried in vacuo. The title compound was isolated in
the form of a colourless solid (26.5 g, 76% yield, 93.8% ee).—mp
215–217 °C. Determination of the enantiomeric purity by CE (see
Section 4.3): tM [(3S)] = 19.9 min/3.1 area %; tM [(3R)] = 20.7 min/
96.9 area %; 93.8% ee. 1H NMR (DMSO-d6, 400 MHz): d = 1.70 (br
s, 1H, 20-Ha), 1.89 (br s, 1H, 20-Hb), 2.22 (s, 3H, C6H4–CH3), 2.30–
3.00 (m, 2H, 10-Ha, 10-Hb), 2.51 (s, 3H, 2-CH3), 2.70 (s, 3H,
N(CH3)2), 2.94 (br s, 3H, N(CH3)2), 3.65 (s, 3H, 3-CH3), 4.71 (br s,
1H, 30-H), 5.04 (br s, 1H, OH), 6.73 (s, 1H, 4-H), 7.09 (mc, 2H,
C6H4–CH3), 7.16 (mc, 1H, C6H4–CH3), 7.42 (mc, 1H, C6H4–CH3),
10.18 (br s, 1H, OH). 13C NMR (DMSO-d6, 100 MHz): d = 13.0
(2-CH3), 18.5 (C6H4–CH3), 24.0 (C-10), 29.7 (3-CH3), 33.9
(CON(CH3)2), 38.3 (CON(CH3)2, C-20), 69.1 (C-30), 97.7 (C-4), 125.3,
125.5, 126.1, 129.7 (C6H4–CH3), 116.3, 131.2, 132.1, 133.7, 135.0,
144.2, 145.8, 150.9 (4 °C), 170.9 (CON(CH3)2). Anal. Calcd for
4.11. 4-Hydroxy-5-{(3R)-3-hydroxy-3-[2-(trifluoromethyl)-
phenyl]propyl}-N,N,1,2-tetramethyl-1H-benzimidazole-6-
carboxamide 2f
Preparation according to Section 4.2: mp 219–221 °C. HPLC
analytical method (see Section 4.5): eluant: methanol/water = 15/
85, 0.8 ml/min, tR (enantiomer 1) = 12.8 min, tR (enantiomer
2) = 17.2 min, tR (1f) = 21.0 min. Determination of the enantio-
meric purity by CE (see Section 4.3): tM [(3S)] = 21.0 min/13.7
area %; tM [(3R)] = 21.4 min/86.3 area %; 72.6% ee. 1H NMR
(DMSO-d6, 200 MHz): d = 1.67 (mc, 1H), 1.89 (mc, 1H), 2.50 (br s,
s), 2.69 (s, 3H), 2.92 (br s, s, 4H), 3.64 (s, 3H), 4.85 (br s, 1H),
5.43 (br s, 1H), 6.70 (s, 1H), 7.43 (mc, 1H), 7.66 (mc, 2H), 7.77
(mc, 1H), 9.93 (br s, 1H).
4.12. 5-[(3R)-3-(2-Ethylphenyl)-3-hydroxypropyl]-4-hydroxy-
N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide 2g
Preparation according to Section 4.2: mp 135–137 °C. HPLC ana-
lytical method (see Section 4.5): eluant: methanol/water = 20/80,
1 ml/min, tR (enantiomer 1) = 13.5 min, tR (enantiomer 2) =
19.4 min, tR (1g) = 28.1 min. Determination of the enantiomeric
purity by CE (see Section 4.3): tM [(3S)] = 20.5 min/6.8 area %; tM
[(3R)] = 21.8 min/93.2 area %; 86.4% ee. 1H NMR (DMSO-d6,
200 MHz): d = 1.12 (t, 3H), 1.75 (br s, 2H), 2.40 (br s), 2.50 (s),
2.58 (q), 2.70, 2.83, 2.94 (s, br s, s, 7H), 3.65 (s, 3H), 4.74 (br s,
1H), 5.01 (br s, 1H), 6.71 (s, 1H), 7.13 (mc, 3H), 7.41 (mc, 1H),
9.75 (br s, 1H).
4.13. 5-[(3R)-3-(4-Fluoro-2-methylphenyl)-3-hydroxypropyl]-
4-hydroxy-N,N,1,2-tetramethyl-1H-benzimidazole-6-
carboxamide 2h
C22H27N3O3: C, 69.27; H, 7.13; N, 11.02. Found: C, 68.98; H, 7.05;
N, 10.52. HRMS (ESI) m/z C22H28N3O3 [M+H]+ calcd: 382.2125,
found: 382.2123.
Preparation according to Section 4.2: foamy solid. HPLC analyt-
ical method (see Section 4.5): eluant: methanol/water = 20/80,
1 ml/min, tR (enantiomer 1) = 17.5 min, tR (enantiomer 2) =
23.7 min, tR (1h) = 19 min. Determination of the enantiomeric
purity by CE (see Section 4.3): tM [(3S)] = 22.5 min/8.4 area %; tM
[(3R)] = 23.7 min/91.6 area %; 83.2% ee. 1H NMR (DMSO-d6,
200 MHz): d = 1.78 (br s, 2H), 2.23 (s, 3H), 2.36 (br s), 2.51 (s),
2.69 (s, 3H), 2.93 (s, br s, 4H), 3.65 (s, 3H), 4.67 (br s, 1H),
5.08 (br s, 1H), 6.71 (s, 1H), 6.96 (mc, 2H), 7.42 (mc, 1H), 9.82 (br
s, 1H).
4.8. 5-[(3R)-3-(2-Fluorophenyl)-3-hydroxypropyl]-4-hydroxy-
N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide 2c
Preparation according to Section 4.2: mp 264–266 °C. 1H NMR
(DMSO-d6, 200 MHz): d = 1.79 (mc, 2H), 2.50 (s, br s), 2.68 (s, br
s, 4H), 2.88 (s, 3H), 3.64 (s, 3H), 4.82 (br t, 1H), 5.26 (br s, 1H),
6.70 (s, 1H), 7.17 (mc, 3H), 7.49 (dt, 1H), 9.80 (br s, 1H).
4.9. 5-[(3R)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-hydroxy-
N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide 2d
4.14. 4-Hydroxy-5-{(3R)-3-hydroxy-3-[2-(methoxymethyl)-
phenyl]propyl}-N,N,1,2-tetramethyl-1H-benzimidazole-6-
carboxamide 2i
Preparation according to Section 4.2: mp 276–277 °C. Determi-
nation of the enantiomeric purity by CE (see Section 4.3): tM
[(3S)] = 21.4 min/6.2 area %; tM [(3R)] = 21.8 min/93.3 area %;
87.6% ee. 1H NMR (DMSO-d6, 200 MHz): d = 1.80 (br s, 2H), 2.40,
2.49 (br s, s), 2.68 (s, br s, 4H), 2.89 (s, 3H), 3.64 (s, 3H), 4.50 (t,
1H), 5.19 (br s, 1H); 6.70 (s, 1H), 7.12 (t, 2H), 7.33 (dd, 2H), 9.90
(br s, 1H).
Preparation according to Section 4.2: foamy solid. HPLC analyt-
ical method (see Section 4.5): eluant: methanol/water: 15/85,
1 ml/min, tR (enantiomer 1) = 9.0 min, tR (enantiomer 2) =
12.0 min, tR (1i) = 15.0 min. Determination of the enantiomeric

2108
A. M. Palmer et al. / Tetrahedron: Asymmetry 19 (2008) 2102–2110
purity by CE (see Section 4.3): tM [(3S)] = 20.4 min/1.3 area %; tM
[(3R)] = 20.6 min/98.7 area %; 97.4% ee. 1H NMR (DMSO-d6,
400 MHz): d = 1.81 (mc, 2H), 2.48 (s, br s), 2.70 (s, 3H), 2.94 (s, br
s, 4H), 3.24 (s, 3H), 3.65 (s, 3H), 4.40 (s, 2H), 4.75 (br s, 1H), 5.04
(br s, 1H), 6.71 (s, 1H), 7.22 (mc, 3H), 7.47 (mc, 1H), 9.76 (br s, 1H).
2H), 3.93 (t, 2H), 4.48 (t, 1H), 5.21 (br s, 1H), 6.81 (s, 1H), 7.26
(mc, 5H), 9.80 (br s, 1H).
4.20. 6-(Azetidin-1-ylcarbonyl)-5-[(3R)-3-hydroxy-3-(2-
methylphenyl)propyl]-1,2-dimethyl-1H-benzimidazol-4-ol 2o
4.15. 5-[(3R)-3-{2-[(Benzyloxy)methyl]phenyl}-3-hydroxy-
propyl]-4-hydroxy-N,N,1,2-tetramethyl-1H-benzimidazole-6-
carboxamide 2j
Preparation according to Section 4.2: foamy solid. HPLC analyt-
ical method (see Section 4.5): eluant: methanol/water = 20/80,
1 ml/min, tR (enantiomer 1) = 14.9 min, tR (enantiomer 2) =
20.4 min, tR (1o) =: 26.0 min. Determination of the enantiomeric
purity by CE (see Section 4.3): tM [(3S)] = 20.9 min/2.4 area %; tM
[(3R)] = 21.7 min/97.6 area %; 95.2% ee. 1H NMR (DMSO-d6,
400 MHz): d = 1.69 (mc, 1H), 1.84 (mc, 1H), 2.16 (mc, 2H), 2.20 (s,
3H), 2.51 (s), 2.65 (mc, 1H), 2.86 (mc, 1H), 3.68 (s, 3H), 3.81 (mc,
2H), 3.96 (mc, 2H), 4.68 (br s, 1H), 5.16 (br s, 1H), 6.83 (s, 1H),
7.09 (mc, 2H), 7.16 (mc, 1H), 7.44 (mc, 1H), 9.78 (br s, 1H).
Preparation according to Section 4.2: foamy solid. Determina-
tion of the enantiomeric purity by HPLC (see Section 4.4): eluant:
n-heptane/ethanol = 70/30, tR [(3R)] = 14.1 min/98.2 area %, tR
[(3S)] = 25.9 min/1.8 area %, 96.4% ee. 1H NMR (DMSO-d6,
400 MHz): d = 1.60–2.02 (br m, 2 H), 2.20–2.63 (br m), 2.50 (s),
2.69 (s, 3H), 2.94 (s, 3H), 3.63 (s, 3H), 4.44 (mc, 4H), 4.76 (br s,
1H), 5.12 (br s, 1H), 6.72 (s, 1H), 7.26 (mc, 8H), 7.48 (mc, 1 H),
9.85 (br s, 1H).
4.21. N-Cyclopropyl-4-hydroxy-5-[(3R)-3-hydroxy-3-(2-
methylphenyl)propyl]-1,2-dimethyl-1H-benzimidazole-6-
carboxamide 2p
4.16. 4-Hydroxy-5-[(3R)-3-hydroxy-3-(2-thienyl)propyl]-
N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide 2k
Preparation according to Section 4.2: mp 299–300 °C. HPLC ana-
lytical method (see Section 4.5): eluant: methanol/water = 20/80,
1 ml/min, tR (enantiomer 1) = 11.0 min, tR (enantiomer 2) =
15.0 min, tR (1p) = 18.0 min. Determination of the enantiomeric
purity by CE (see Section 4.3): tM [(3S)] = 22.0 min/0.8 area %; tM
[(3R)] = 23.1 min/99.2 area %; 98.4% ee. 1H NMR (DMSO-d6,
200 MHz): d = 0.54 (mc, 2H), 0.65 (mc, 2H), 1.75 (mc, 2H), 2.21 (s,
3H), 2.50 (s), 2.80 (mc, 3H), 3.66 (s, 3H), 4.65 (t, 1H), 5.19 (d, 1H),
6.85 (s, 1H), 7.10 (mc, 3H), 7.43 (mc, 1H), 8.17 (d, 1H), 9.63 (br s,
1H).
Preparation according to Section 4.2: mp 264–265 °C. Determi-
nation of the enantiomeric purity by HPLC (see Section 4.4): elu-
ant: n-heptane/ethanol = 80/20, tR [(3R)] = 21.0 min/88.8 area %, tR
[(3S)] = 23.1 min/9.9 area %, 79.9% ee. 1H NMR (DMSO-d6,
200 MHz): d = 1.92 (br s, 2H), 2.50 (s), 2.71 (s, br s, 4H), 2.95 (s,
3H), 3.65 (s, 3H), 4.73 (br t, 1H), 5.48 (br s, 1H), 6.72 (s, 1H), 6.95
(mc, 2H), 7.37 (dd, 1H), 9.80 (br s, 1H).
4.17. 4-Hydroxy-5-[(3R)-3-hydroxy-3-(2-methyl-3-thienyl)-
propyl]-N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide
2l
4.22. 4-Hydroxy-5-[(3R)-3-hydroxy-3-phenylpropyl]-N,1,2-
trimethyl-1H-benzimidazole-6-carboxamide 2q
Preparation according to Section 4.2: foamy solid. HPLC analyt-
ical method (see Section 4.5): eluant: methanol/water = 20/80,
1 ml/min, tR (both enantiomers) = 7.0 min, tR (1l) = 10.0 min.
Determination of the enantiomeric purity by CE (see Section 4.3):
tM [(3S)] = 20.0 min/2.1 area %; tM [(3R)] = 21.0 min/97.9 area %;
95.8% ee. 1H NMR (CDCl3, 200 MHz): d = 2.10, 2.24 (br s, br s,
5H), 2.59, 2.63 (s, br s, 4H), 2.82 (s, 3H), 3.12, 3.14 (br s, s,
4H), 3.67 (s, 3H), 4.64 (mc, 1H), 6.69 (s, 1H), 6.96 (d, 1H), 7.03 (d,
1H).
Preparation according to Section 4.2: mp 247–249 °C. Determi-
nation of the enantiomeric purity by CE (see Section 4.3): tM
[(3S)] = 24.5 min/11.7 area %; tM [(3R)] = 25.3 min/87.7 area %;
76.5% ee. 1H NMR (DMSO-d6, 200 MHz): d = 1.85 (mc, 2H), 2.50,
2.53 (s, mc), 2.71, 2.77 (d, mc, 4H), 3.66 (s, 3H), 4.46 (br t, 1H),
5.25 (br s, 1H), 6.88 (s, 1H), 7.25 (mc, 5H), 8.00 (q, 1H), 9.70 (br s,
1H).
4.23. 4-Hydroxy-5-[(3R)-3-hydroxy-3-(2-methylphenyl)-
propyl]-N,1,2-trimethyl-1H-benzimidazole-6-carboxamide 2r
4.18. 5-[(3R)-3-Hydroxy-3-(2-methylphenyl)propyl]-1,2-
dimethyl-6-(pyrrolidin-1-ylcarbonyl)-1H-benzimidazol-4-ol 2m
Preparation according to Section 4.2: mp 238–240 °C. HPLC ana-
lytical method (see Section 4.5): eluant: methanol/water = 20/80,
1 ml/min, tR (enantiomer 1) = 18.0 min, tR (enantiomer 2) =
25.0 min, tR (1r) = 27.0 min. Determination of the enantiomeric
purity by CE (see Section 4.3): tM [(3S)] = 20.7 min/2.6 area %; tM
[(3R)] = 21.7 min/94.7 area %; 94.7% ee. 1H NMR (DMSO-d6,
400 MHz): d = 1.67 (mc, 1H), 1.87 (mc, 1H), 2.18 (s, 3H), 2.50 (s),
2.70, 2.72 (mc, d, 4H), 2.91 (mc, 1H), 3.66 (s, 3H), 4.66 (mc, 1H),
5.23 (d, 1H), 6.89 (s, 1H), 7.07 (mc, 2H), 7.14 (mc, 1H), 7.43 (d,
1H), 8.05 (q, 1H), 9.69 (br s, 1H).
Preparation according to Section 4.2: HPLC analytical method
(see Section 4.5): eluant: methanol/water = 20/80, 1 ml/min, tR
(enantiomer 1) = 21.8 min, tR (enantiomer 2) = 30.9 min, tR
(1m) = 32.0 min. Determination of the enantiomeric purity by CE
(see Section 4.3): tM [(3S)] = 21.0 min/4.6 area %; tM [(3R)] =
21.7 min/95.4 area %; 90.8% ee. 1H NMR (DMSO-d6, 400 MHz):
d = 1.71 (mc, 3H), 1.82 (mc, 3H), 2.22 (s, 3H), 2.50 (br s), 2.60 (s,
3H), 2.78 (br s, 1H), 3.00 (br s, 2H), 3.38 (mc, 2H), 3.72 (s, 3H),
4.72 (t, 1H), 5.17 (br s, 1H), 6.97 (s, 1H), 7.13 (mc, 3H), 7.40 (d,
1H), 9.92 (br s, 1H).
4.24. 5-[(3R)-3-Hydroxy-3-(2-methylphenyl)propyl]-6-
(methoxymethyl)-1,2-dimethyl-1H-benzimidazol-4-ol 2s
4.19. 6-(Azetidin-1-ylcarbonyl)-5-[(3R)-3-hydroxy-3-phenyl-
propyl]-1,2-dimethyl-1H-benzimidazol-4-ol 2n
Preparation according to Section 4.2: foamy solid. Determina-
tion of the enantiomeric purity by HPLC (see Section 4.4): eluant:
n-hexane/isopropanol = 80/20, tR [(3R)] = 16.9 min/99.1 area %, tR
[(3S)] = 19.2 min/0.9 area %, 98.2% ee. 1H NMR (DMSO-d6,
200 MHz): d = 1.76 (mc, 2H), 2.21 (s, 3H), 2.49 (s), 2.64 (mc, 1H),
2.81 (mc, 1H), 3.22 (s, 3H), 3.64 (s, 3H), 4.39 (s, 2H), 4.75 (br t,
Preparation according to Section 4.2: mp 265–266 °C. Determi-
nation of the enantiomeric purity by CE (see Section 4.3): tM
[(3S)] = 23.1 min/7.6 area %; tM [(3R)] = 23.8 min/92.4 area %;
84.8% ee. 1H NMR (DMSO-d6, 200 MHz): d = 1.83 (mc, 2H), 2.15
(mc, 2H), 2.50, 2.55 (s, mc), 2.77 (mc, 1H), 3.66 (s, 3H), 3.80 (t,

A. M. Palmer et al. / Tetrahedron: Asymmetry 19 (2008) 2102–2110
2109
1H), 5.04 (br d, 1H), 6.84 (s, 1H), 7.14 (mc, 3H), 7.46 (d, 1H), 9.49 (br
s, 1H).
4.27. (6Z)-8-Hydroxy-6-[hydroxy(2-methylphenyl)methylene]-
2,3-dimethyl-6,7-dihydroindeno[5,6-d]imidazol-5(3H)-one 12b
In a flask filled with argon, ketone 1b (3.5 g, 9.2 mmol) was dis-
solved in 2-PrOH (34 ml) and t-BuOK solution (1 M in t-BuOH,
16 ml) was slowly added. The suspension was stirred for 30 min
4.25. (8S)-N,N,2,3-Tetramethyl-8-phenyl-3,6,7,8-tetra-
hydrochromeno[7,8-d]imidazole-5-carboxamide 3a
at rt and catalyst 9 (46 mg, 37 lmol, S/C 250:1) was added. The
To a suspension of diol 2a (1.3 g, 3.5 mmol) and PPh3 (2.7 g,
10.2 mmol) in THF (60 ml), DIAD (2.1 ml, 10.5 mmol) was added
and the mixture stirred for 15 min at rt. The reaction was
concentrated in vacuo, the residue was treated with satd NH4Cl
solution (100 ml) and extracted with ethyl acetate (2 ꢁ 100 ml).
The combined organic phases were washed with saturated NH4Cl
solution (20 ml) and H2O (20 ml), dried over MgSO4 and
concentrated in vacuo. The crude product was purified by column
chromatography [SiO2, eluant: EtOAc/MeOH = 9:1 (v/v)] to afford
1.03 g of the title compound. Crystallization from diisopropyl ether
(20 ml) furnished the pure title compound 3a (0.95 g of a white so-
lid, 77% yield; 95.8% ee): mp 226–227 °C. Determination of the
enantiomeric purity by CE (capillary: Agilent bubble-cell 64.5
reaction mixture was transferred into a 100 ml Premex Hastelloy
autoclave, and hydrogenated at 70 °C and 80 bar pressure for
22 h. After cooling to rt and releasing of the H2-pressure, the sus-
pension was poured into a mixture of satd NH4Cl solution (80 ml)
and CH2Cl2 (200 ml). The phases were separated and the aq phase
was extracted with CH2Cl2 (2 ꢁ 30 ml). The combined organic
phases were washed with water (50 ml), dried over sodium sulfate
and concentrated in vacuo. The residue (3.2 g of a green foam) was
purified by column chromatography [SiO2, eluant: CH2Cl2/
MeOH = 10:1 (v/v)]. The title compound 12b was eluted first and
purified further by crystallization from acetone (520 mg of a yel-
low solid, mp 267–269 °C, 17% yield). The chiral alcohol 2b was
eluted next and crystallized from acetone to afford 1.6 g (45%
yield) of a colourless solid (mp 205–206 °C). In DMSO-d6 a mixture
of the enol tautomer of 12b and the diketo tautomer of 12b was
observed (87:13 ratio). If traces of MeOH were added, the 6-H sig-
nal of the diketo form was quenched, whereas the ratio of tautom-
ers remained the same. 1H NMR signals of the enol tautomer of
12b (DMSO-d6, 400 MHz): d = 2.39 (s, 3H, C6H4–CH3), 2.57 (s, 3H,
2-CH3), 3.43 (s, 2H, 7-H), 3.77 (s, 3H, 3-CH3), 7.28–7.48 (mc, 4H,
4-H, C6H4–CH3), 7.57 (mc, 1H, C6H4–CH3). 13C NMR signals of the
enol tautomer of 12b (DMSO-d6, 100 MHz): d = 13.5 (2-CH3), 19.3
(C6H4–CH3), 26.8 (C-7), 30.0 (3-CH3), 95.6 (C-4), 111.7 (C-6),
125.7, 128.3, 129.9, 131.1 (C6H4–CH3), 125.9, 132.7, 134.1, 135.8,
136.3, 137.7, 144.0, 153.9 (4 °C), 171.8 (HO-C@C), 195.1 (C@O).
1H NMR signals of the diketo tautomer of 12b (DMSO-d6,
400 MHz): d = 2.37 (s, 3H, C6H4–CH3), 2.57 (s, 3H, 2-CH3), 3.25-
3.40 (m, 2H, 7-H), 3.74 (s, 3H, 3-CH3), 4.98 (mc, 1 H, 6-H), 7.28–
7.48 (mc, 4H, 4-H, C6H4–CH3), 7.96 (mc, 1H, C6H4–CH3). 13C NMR
signals of the diketo tautomer of 12b (DMSO-d6, 100 MHz):
d = 13.5 (2-CH3), 20.6 (C6H4–CH3), 26.5 (C-7), 30.0 (3-CH3), 59.4
(C-6), 96.0 (C-4), 125.8, 129.8, 130.4, 130.6, 131.5, 137.2, 137.6,
137.9, 144.1, 154.6 (C6H4–CH3, 4 °C), 200.0 (C@O), 200.6 (C@O).
Anal. Calcd for C20H18N2O3: C, 71.84; H, 5.43; N, 8.38. Found: C,
71.70; H, 5.44; N, 8.34. HRMS (ESI) m/z C20H19N2O3 [M+H]+ calcd:
335.1390, found: 335.1398.
cm ꢁ 50
lm; buffer: 50 mM sodium phosphate, pH 2.5; chiral
selector: 40 mM heptakis(2,3,6-tri-O-methyl)-b-cyclodextrin;
30 kV; 20 °C): tM [(8S)] = 19.7 min/97.9 area %; tM [(8R)] =
21.0 min/2.1 area %; 95.8% ee. 1H NMR (DMSO-d6, 400 MHz):
d = 2.08 (mc, 1H, 7-Ha), 2.23 (mc, 1H, 7-Hb), 2.47 (s, 3H, 2-CH3),
2.55 (mc, 1H, 6-Ha), 2.77, 2.81 (s, mc, 4H, CON(CH3)2, 6-Hb), 3.00
3
(s, 3H, CON(CH3)2), 3.67 (s, 3H, 3-CH3), 5.21 (dd, J7,8 = 9.8 Hz,
3J7,8 = 2.0 Hz, 1H, 8-H), 6.92 (s, 1H, 4-H), 7.34 (mc, 1H, Ph), 7.41
(mc, 2H, Ph), 7.47 (mc, 2H, Ph). 13C NMR (DMSO-d6, 100 MHz):
d = 13.3 (2-CH3), 21.6 (C-6), 28.8 (C-7), 29.7 (3-CH3), 33.9, 37.9
(CON(CH3)2), 76.6 (C-8), 99.4 (C-4), 126.0, 127.7, 128.3 (Ph),
109.6, 131.0, 131.5, 135.4, 141.4, 145.3, 151.2 (4 °C), 170.0
(CON(CH3)2). Anal. Calcd for C21H23N3O2: C, 72.18; H, 6.63; N,
12.03. Found: C, 72.27; H, 6.69; N, 12.02. HRMS (ESI) m/z
C
21H24N3O2 [M+H]+ calcd: 350.1863, found: 350.1853.
4.26. (8S)-N,N,2,3-Tetramethyl-8-(2-methylphenyl)-3,6,7,8-
tetrahydrochromeno[7,8-d]imidazole-5-carboxamide 3b
To a suspension of diol 2b (26.0 g, 68.1 mmol) and PPh3 (35.0 g,
133 mmol) in dry THF (600 ml), DIAD (27.7 ml, 27.0 g, 134 mmol)
was added over a period of 10 min. A yellow solution was ob-
tained, which was stirred for 5 min at rt and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy [SiO2, eluant: EtOAc/MeOH = 100:2 (v/v)]. Evapouration of
the corresponding fractions afforded the title compound 3b in
4.28. (6Z)-8-Hydroxy-6-[hydroxy(2-chlorophenyl)methylene]-
2,3-dimethyl-6,7-dihydroindeno[5,6-d]imidazol-5(3H)-one 12e
84% corrected yield (23.0 g of
a colourless foam containing
Mp 277–279 °C. 1H NMR (DMSO-d6, 200 MHz): d = 2.57 (s, 3H),
3.46 (s, 2H), 3.78 (s, 3H), 7.49 (s, 1H), 7.55 (mc, 2H), 7.67 (mc, 2H),
10.11 (br s, 1H), mixture of enol form and diketo form (93:7), only
1H NMR signals of enol form reported.
10 wt-% of EtOAc, 95.6% ee). After intense drying in vacuo, an
amorphous solid was obtained: mp 126–128 °C. Determination
of the enantiomeric purity by HPLC (column: Daicel Chiralpak
AD-H, 250 ꢁ 4.6 mm, 5
lm; eluant: n-heptane/EtOH: 80:20 (v/v);
flow rate: 1 ml/min, detection at 218 nm): tR [(8R)] = 10.2 min/
2.2 area %, tR [(8S)] = 13.7 min/97.8 area %, 95.6% ee. 1H NMR
(DMSO-d6, 400 MHz): d = 1.98 (mc, 1H, 7-Ha), 2.22 (mc, 1H, 7-Hb),
2.38 (s, 3H, C6H4–CH3), 2.49 (s, 3H, 2-CH3), 2.62 (br s, 1H, 6-Ha),
2.81 (s, 3H, CON(CH3)2), 2.90 (br s, 1H, 6-Hb), 3.02 (s, 3H,
4.29. (6Z)-8-Hydroxy-6-[hydroxy(2-trifluorophenyl)-
methylene]-2,3-dimethyl-6,7-dihydroindeno[5,6-d]imidazol-
5(3H)-one 12f
3
1H NMR (DMSO-d6, 200 MHz): d = 2.57 (s, 3H), 3.38 (s, 2H), 3.78
(s, 3H), 7.48 (s, 1H), 7.86 (mc, 4H), 10.09 (br s, 1H), mixture of enol
form and diketo form (88:12), only 1H NMR signals of enol form
reported.
CON(CH3)2), 3.67 (s, 3H, 3-CH3), 5.32 (dd, J7,8 = 10.4 Hz,
3J7,8 = 1.9 Hz, 1H, 8-H), 6.92 (s, 1H, 4-H), 7.24 (mc, 3H, C6H4–
CH3), 7.47 (mc, 1H, C6H4–CH3). 13C NMR (DMSO-d6, 100 MHz):
d = 13.2 (2-CH3), 18.6 (C6H4–CH3), 22.2 (C-6), 27.8 (C-7), 29.7 (3-
CH3), 33.9, 37.9 (CON(CH3)2), 74.3 (C-8), 99.4 (C-4), 125.6, 125.9,
127.5, 130.2 (C6H4–CH3), 109.7, 131.0, 131.5, 134.8, 135.3, 139.3,
145.7, 151.2 (4 °C), 170.0 (CON(CH3)2). Anal. Calcd for
4.30. (6Z)-8-Hydroxy-6-[hydroxy(2-ethylphenyl)methylene]-
2,3-dimethyl-6,7-dihydroindeno[5,6-d]imidazol-5(3H)-one 12g
C
22H25N3O2: C, 72.70; H, 6.93; N, 11.56. Found: C, 72.71; H, 6.90;
N, 11.55. HRMS (ESI) m/z C22H26N3O2 [M+H]+ calcd: 364.2020,
Mp 258–260 °C. 1H NMR (DMSO-d6, 200 MHz): d = 1.16 (t, 3H),
found: 364.2010.
2.57 (s, 3H), 2.73 (q, 2H), 3.40 (s, 2H), 3.78 (s, 3H), 7.42, 7.47 (mc, s,

2110
A. M. Palmer et al. / Tetrahedron: Asymmetry 19 (2008) 2102–2110
2. Palmer, A. M.; Grobbel, B.; Jecke, C.; Brehm, C.; Zimmermann, P. J.; Buhr, W.;
Feth, M. P.; Simon, W.-A.; Kromer, W. J. Med. Chem. 2007, 50, 6240–6264.
3. (a) Zimmermann, P. J.; Brehm, C.; Buhr, W.; Palmer, A. M.; Volz, J.; Simon, W. A.
Bioorg. Med. Chem. 2008, 16, 536–541; (b) Palmer, A. M.; Münch, G.; Brehm, C.;
Zimmermann, P. J.; Buhr, W.; Feth, M. P.; Simon, W. A. Bioorg. Med. Chem. 2008,
16, 1511–1530.
4. (a) Palmer, A. M.; Nettekoven, U. Tetrahedron: Asymmetry 2007, 18, 2381–2385;
(b) Palmer, A. M.; Nedden, H.; Zanotti-Gerosa, A. Tetrahedron: Asymmetry 2008,
19, 1310–1327.
5H), 10.10 (br s, 1H), mixture of enol form and diketo form (91:9),
only 1H NMR signals of enol form reported.
4.31. (6Z)-8-Hydroxy-6-[hydroxy(4-fluoro-2-methylphenyl)-
methylene]-2,3-dimethyl-6,7-dihydroindeno[5,6-d]imidazol-
5(3H)-one 12h
Mp 296–297 °C. 1H NMR (DMSO-d6, 200 MHz): d = 2.40 (s, 3H),
2.57 (s, 3H), 3.43 (s, 2H), 3.78 (s, 3H), 7.23 (mc, 2H), 7.47 (s, 1H),
7.65 (mc, 1H), 10.12 (br s, 1H), mixture of enol form and diketo
form (84:16), only 1H NMR signals of enol form reported.
5. Chiesa, V.; Palmer, A.; Buhr, W.; Zimmermann, P. J.; Brehm, C.; Simon, W.-A.;
Postius, S.; Kromer, W.; Zanotti-Gerosa, A. International patent application WO
2006/136552.
6. (a) Doucet, H.; Ohkuma, T.; Murata, K.; Yokozawa, T.; Kozawa, M.; Katayama,
E.; England, A. F.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. 1998, 37, 1703–
1707; (b) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40–73; (c)
Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008–2022; (d) Noyori, R.; Kitamura,
M.; Ohkuma, T. PNAS 2004, 101, 5356–5362.
Acknowledgements
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1751; (b) Chen, C.; Reamer, R. A.; Chilenski, J. R.; McWilliams, C. J. Org. Lett.
2003, 5, 5039–5042; (c) O’Shea, P. D.; Chen, C.; Chen, W.; Dagneau, P.; Frey, L.
F.; Grabowski, E. J. J.; Marcantonio, K. M.; Reamer, R. A.; Tan, L.; Tillyer, R. D.;
Roy, A.; Wang, X.; Zhao, D. J. Org. Chem. 2005, 70, 3021–3030; (d) Blaser, H.-U.;
Spindler, F.; Studer, M. Appl. Catal. A 2001, 221, 119–143; (e) Blaser, H.-U.;
Pugin, B.; Spindler, F. J. Mol. Catal. A 2005, 231, 1–20.
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Chem. 2002, 67, 7908–7910; (b) Wu, J.; Ji, J.-X.; Guo, R.; Yeung, C.-H.; Chan, A. S.
C. Chem. Eur. J. 2003, 9, 2963–2968.
9. (a) Chalabi, P. M.; Spindler, F.; Nettekoven, U.; Lotz, M.; Schnyder, A.; Siegrist,
U.; Blaser, H.-U.; Thommen, M. sp2 2007, 30–33; (b) Chalabi, P. M.; Spindler, F.;
Nettekoven, U.; Lotz, M.; Schnyder, A.; Siegrist, U.; Blaser, H.-U.; Thommen, M.
sp2 2007, 40–42; (c) Jäkel, C.; Paciello, R. Chem. Rev. 2006, 106, 2912–2942.
10. For detailed examples of ligands belonging to the different structural classes
see www.solvias.com/documents/Dokumente/Downloads_prodserv/Liganden_
Kit_List.pdf.
We are grateful to Mr. Jens Bruchhaus, Mr. Reinhard Geiger, Mr.
Oliver Meyer, Ms. Anja Schmid, Mr. Burkhard Grobbel, Ms. Cornelia
Jecke and Ms. Gabriela Münch (all from NYCOMED GmbH) for
chemical assistance and to Ms. Tanja Ramisch and Mr. Volker Horn
(both from NYCOMED GmbH) for the assessment of compound
purities. We thank Dr. P. Dünkelmann and Dr. T. Deußmann (Julich
Chiral Solutions GmbH) for the investigation of the enzymatic cat-
alytic reduction of ketone 1b.
References
1. Modlin, I. M.; Sachs, G. Acid Related Diseases: Biology and Treatment; Schnetztor:
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11. Dünkelmann, P.; Deußmann, T. Unpublished results.