Preparation of tricyclic imidazopyridines by asymmetric ketone hydrogenation in the presence of ruthenium phosphino-oxazoline catalyst

Article abstract of DOI:10.1016/j.tetasy.2007.10.013

The asymmetric hydrogenation of the prochiral heterocyclic ketone 2 and its O-protected analogues 9 to 11 in the presence of the ruthenium POX catalyst RuCl₂(PPh₃)(Ph₂P-Fc-oxaⁱPr) was studied. The reactivity of

Full text of DOI:10.1016/j.tetasy.2007.10.013

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2381–2385
Preparation of tricyclic imidazopyridines by asymmetric
ketone hydrogenation in the presence of ruthenium
phosphino-oxazoline catalyst
Andreas M. Palmera,* and Ulrike Nettekovenb,*
aNYCOMED GmbH, Department of Medicinal Chemistry, Byk-Gulden-Str. 2, D-78467 Konstanz, Germany
bSolvias AG, Department of Synthesis and Catalysis, Mattenstraße 22, CH-4002 Basel, Switzerland
Received 26 September 2007; accepted 10 October 2007
Abstract—The asymmetric hydrogenation of the prochiral heterocyclic ketone 2 and its O-protected analogues 9 to 11 in the presence of
the ruthenium POX catalyst RuCl2(PPh3)(Ph2P-Fc-oxaiPr) was studied. The reactivity of the substrate and the enantioselectivity of the
reduction depended on the nature of the protecting group. The best results were achieved with the thexyldimethylsilyl protecting group:
The corresponding alcohol 13 was obtained in 86% yield and 88% ee and constitutes a valuable intermediate for the synthesis of the
potassium-competitive acid blocker BYK 311319 1.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
311319 1 as a potent inhibitor of the H+/K+-ATPase show-
ing promising pharmaceutical activity.8,9 A key step in the
synthesis of the enantiopure P-CAB 1 is the asymmetric
reduction of ketone 2 and subsequent Mitsunobu cycliza-
tion of the resulting diol 3 (Scheme 1).8,9
Acid related diseases, such as gastroesophageal reflux dis-
ease (GERD) and peptic ulcer disease, have a high preva-
lence and represent a large economic burden.1–3 The
reduction of acid secretion by inhibition of the gastric pro-
ton pump enzyme (H+/K+-ATPase) constitutes an effective
approach for the treatment of these medical conditions.1–3
With the introduction of proton pump inhibitors (PPis),
which inhibit the H+/K+-ATPase in an irreversible man-
ner, highly effective therapeutic agents have become
available. Despite the clear success of PPis, such as
omeprazole, esomeprazole, lansoprazole, pantoprazole,
rabeprazole, or tenatoprazole, several pharmaceutical
companies are currently engaged in the development of
potassium-competitive acid blockers (P-CABs). Due to
their new mode of action (reversible inhibition of
H+/K+-ATPase), P-CABs might be able to overcome some
limitations encountered during the treatment with PPis.4–7
A variety of methods for the asymmetric reduction of
ketones are currently available, including enzymatic trans-
formations,10 hydrosilylation,11,12 hydroboration,13–16
transfer hydrogenation,17,18 and hydrogenation.19,20 In the
field of enantioselective homogeneous hydrogenation, the
Noyori Ru-PP-NN systems of the type RuCl2[diphos-
phine][diamine] in the presence of base constitute the most
prominent (pre)catalysts and excellent results have been
published for aromatic ketone substrates in recent
years.19,20 Consequently, one of the most active and selec-
tive catalysts, RuCl2[(S)-BINAP][(S)-DAIPEN] 4, was
tested in the presence of potassium tert-butylate for the
asymmetric hydrogenation of 2. Under optimized condi-
tions and using an S/C ratio of 130:1, chiral alcohol 3 could
be prepared with an enantiomeric purity of 85% ee.8,9 While
this result was encouraging, we were still aiming at the iden-
tification of an alternative, more selective system for the
asymmetric reduction of ketone 2. Herein we report the
preparation of alcohol 3 using the ruthenium POX (phos-
phino-oxazoline) catalyst system RuCl2(PPh3)(Ph2P-Fc-
oxaiPr) 5 depicted in Figure 1.21–24 Upon activation with
base, complexes of the type RuCl2(PPh3)(aminophosphine)
Over the course of our P-CAB led optimization program,
we identified the tricyclic imidazo[1,2-a]pyridine BYK
*
Corresponding authors. Tel.: +49 7531 844783; fax: +49 7531 8492087
(A.M.P.); tel.: +41 61 686 6161; fax: +41 61 686 6311 (U.N.); e-mail
addresses: andreas.palmer@nycomed.com; ulrike.nettekoven@solvias.
com
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.013

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A. M. Palmer, U. Nettekoven / Tetrahedron: Asymmetry 18 (2007) 2381–2385
O
O
O
N
N
N
N
N
N
N
N
N
O
OH
HO
OH
O
Ph
Ph
Ph
2
3
1
Scheme 1.
OMe
O
Ph
Ph
H H
N
Cl
Cl
Ph
Ph
Ph
P
N
OMe
P
Ru
Cl
P
Ru
Fe
P
N
Ph Ph
Cl
Ph Ph
H H
4
5
Figure 1. Structure of the hydrogenation catalysts RuCl2[(S)-BINAP][(S)-DAIPEN] 4 and RuCl2(PPh3)(SC,Sm)-(Ph2P-Fc-oxaiPr) 5.
are productive and selective catalysts for a range of different
substrates.
respective functionalities in 8-hydroxychinoline 8) to ruthe-
nium effectively block catalyst activity. Better results can be
obtained with protected substrates and, consequently, phe-
nolic ketone 2 was transformed into the corresponding
benzyl ether 9, silyl ether 10, or pivaloyl ester 11, respec-
tively (Scheme 3).
2. Results and discussion
First, we investigated the asymmetric reduction of ketone 2
in the presence of precatalyst 5 and either sodium hydrox-
ide or potassium tert-butylate as base. Since in neither case
significant conversion was observed, it was envisaged that
the free phenol moiety of ketone 2 might interfere with
catalysis. This hypothesis was corroborated by test experi-
ments: acetophenone 6 was hydrogenated using complex 5
and sodium hydroxide as a base in toluene. These condi-
tions usually allow for full conversion at S/C ratios of up
to 50,000:1 and (1R)-1-phenylethanol 7 is obtained with
an enantiomeric purity of >98% ee.22–24 When this hydro-
genation was carried out, however, at S/C = 100:1 in the
presence of 1 mol % of 8-hydroxychinoline 8, no conver-
sion of acetophenone 6 was observed (Scheme 2).
The asymmetric reduction of the O-benzyl-protected
ketone 9 in the presence of POX catalyst 5 was studied first.
On a 0.5 mmol scale, the reaction was feasible at substrate
to catalyst ratios (S/C ratios) of up to 200:1 (Table 1,
entries 1–3). Quantitative conversion of the starting mate-
rial 9 was observed and the corresponding alcohol 12 was
formed selectively with an enantiomeric purity of 83% ee.
The hydrogenation reaction could be conducted at either
40 °C or at room temperature, showing no effect on the
ee value (entries 2 and 3). At an S/C ratio of 300:1, the con-
version was incomplete (70%), whereas the enantiomeric
purity remained unchanged (83% ee, entry 4). On a 5 mmol
scale, the reduction of ketone 9 was run at a higher dilution
in the presence of more hydrogenation catalyst and base
(entry 5). Quantitative conversion of the starting material
9 occurred within a period of three days and the benzyl-
protected alcohol 12 was isolated in 96% yield with an
enantiomeric purity of 78% ee.
Presumably, the coordination of the phenol moiety and the
neighbouring aromatic nitrogen of substrate 2 (or the
O
OH
For reasons of comparison, we also conducted a prelimin-
ary experiment of the reduction of ketone 9 in the presence
of Noyori catalyst 4 (Scheme 3): hydrogenation using
1 mol % of RuCl2[(S)-BINAP][(S)-DAIPEN] and potas-
sium tert-butylate afforded alcohol 12 in 79% yield and
75% ee.
(i)
X
6
7
N
OH
8
Although the observation of hydrogenation activity for the
benzyl protected substrate 9 proved the assumption of the
phenol group acting as a catalyst deactivator for Ru-POX
Scheme 2. Reagents and conditions: (i) 1 mol % RuCl2(PPh3)(Ph2P-Fc-
oxaiPr), 1 mol % 8, NaOH, toluene, H2O, H2, no conversion.

A. M. Palmer, U. Nettekoven / Tetrahedron: Asymmetry 18 (2007) 2381–2385
2383
O
O
N
N
N
N
(i) or (ii),
or (iii)
N
N
O
OH
O
O
PG
Ph
Ph
9 (PG = Bn)
10 (PG = TxDMS)
11 (PG = Piv)
2
(iv) or (v)
(vi) or (vii)
X
O
O
N
N
N
N
N
(viii)
N
or (ix)
HO
OH
HO
O
PG
Ph
Ph
3
12 (PG = Bn)
13 (PG = TxDMS)
Scheme 3. Reagents and conditions: (i) preparation of 9: K2CO3, BnCl, DMF, 55 °C, 5 h, 96%; (ii) preparation of 10: TxDMSCl, imidazole, DMF, rt, 1 h,
94%; (iii) preparation of 11: PivCl, K2CO3, acetone, rt, 2 h, 69%; (iv) 2 mol % RuCl2(PPh3)(Ph2P-Fc-oxaiPr), NaOH, toluene, H2O, 80 bar H2, 80 °C, 24 h,
<5% conversion; (v) 2 mol % RuCl2(PPh3)(Ph2P-Fc-oxaiPr), KOtBu, 2-PrOH, 80 bar H2, rt, 66 h, <5% conversion; (vi) RuCl2(PPh3)(Ph2P-Fc-oxaiPr),
NaOH, toluene, H2O, see Table 1; (vii) reduction of 9: 1 mol % RuCl2[(S)-BINAP][(S)-DAIPEN], KOtBu, 2-PrOH, 40 bar H2, rt, 22 h, 79%, 75% ee; (viii)
cleavage of benzyl protecting group: Pd/C, 1,4-cyclohexadiene, EtOH, 80 °C, 2 h, 83%; (ix) cleavage of silyl protecting group: TBAF, THF, rt, 5 h, 86%.
Table 1. Asymmetric reduction of O-protected ketones 9, 10, and 11 in the presence of RuCl2(PPh3)(Ph2P-Fc-oxaiPr) 5
Entry
SM
Scale (mmol)
S/C ratio
Toluene (ml)/1 N NaOH (ml)
Conditions
Conversiond (%)
eed,e (%)
1
2
3
4
5
9
9
9
9
9
0.5
0.5
0.5
0.5
5.0
100:1
200:1
200:1
300:1
20:1
3/1
3/1
3/1
3/1
80 bar H2, 40 °C, 18 ha
80 bar H2, 40 °C, 15 ha
80 bar H2, rt, 16 ha
100
100
100
70
83
83
83
83
78
80 bar H2, rt, 16 ha
180/60
80 bar H2, 40 °C, 3 db
100
6
7
8
10
10
10
10
10
10
10
10
10
10
0.5
0.5
0.5
0.5
1.0
0.5
0.5
0.5
1.0
5.0
100:1
200:1
400:1
400:1
400:1
400:1
500:1
500:1
500:1
20:1
3/1
3/1
3/1
3/1
5/2
3/0.5
2/1
2/1
5/2
80 bar H2, 40 °C, 16 ha
80 bar H2, 40 °C, 17 ha
80 bar H2, 40 °C, 16 ha
40 bar H2, 40 °C, 22 ha
80 bar H2, 40 °C, 16 hc
80 bar H2, 40 °C, 16 ha
80 bar H2, 40 °C, 65 ha
80 bar H2, rt, 65 hc
100
100
90
100
100
33
67
80
78
100
90
89
90
90
90
90
88
89
90
88
9
10
11
12
13
14
15
80 bar H2, 40 °C, 67 hc
180/60
80 bar H2, 40 °C, 3 db
16
11
0.5
200:1
4/1
80 bar H2, 40 °C, 66 ha
<5
—
a 50 ml autoclave with stirring bar.
b 1 l autoclave with glass inlay.
c 50 ml TOP autoclave (magnet driven propeller stirrer).
d Determined by chiral HPLC.
e Absolute configuration of 12 and 13: (R) (see Refs. 8 and 9).

2384
A. M. Palmer, U. Nettekoven / Tetrahedron: Asymmetry 18 (2007) 2381–2385
type systems, stereoselectivities still remained lower than
obtained for the unprotected ketone starting material.
Therefore, we turned our attention toward the asymmetric
hydrogenation of the silyl-protected ketone 10 in the pres-
ence of ruthenium POX catalyst 5. Again, quantitative con-
version of the starting material 10 was observed at S/C
ratios of 100:1 and 200:1 (Table 1, entries 6 and 7). To
our delight, the silyl-protected alcohol 13 was obtained in
better enantiomeric purity than its benzyl-protected ana-
logue 12 (90% ee vs 83% ee). At an S/C ratio of 400:1,
the reduction of ketone 10 still proceeded smoothly and
with high enantioselectivity. The reduction could be con-
ducted at hydrogen pressures of 80 bar (entry 8) or
40 bar (entry 9). At these low catalyst concentrations, the
use of propeller-stirring enabling more efficient hydrogen
mixing in comparison to magnetic stirring seemed to be
advantageous (entry 10). The stoichiometry of base is cru-
cial for the outcome of the hydrogenation reaction: In the
presence of 1 equiv of the base, only 33% conversion was
obtained (entry 11), whereas the reduction proceeded in a
nearly quantitative manner, when 2 equiv of base were em-
ployed (entries 8–10). At an S/C ratio of 500:1, the conver-
sion of starting material 10 did not exceed 80% even after
an extended reaction period of three days (entries 12–14).
Again, the use of propeller-stirring (entries 13 and 14)
was beneficial, whereas little effect on conversion and ee
was observed by employing slightly different concentra-
tions and reaction temperatures. The reduction of silyl-pro-
tected ketone 10 was also feasible on a 5 mmol scale. Due
to the higher dilution of substrate 10, more hydrogenation
catalyst and base was employed (entry 15). The corre-
sponding alcohol 13 was isolated in 86% yield and pos-
sessed an enantiomeric purity of 88% ee.
with the unprotected ketone 2 or in the presence of a pro-
tecting group, protection of the phenol moiety is crucial for
the successful hydrogenation using ruthenium POX cata-
lyst 5. Hydrogenation of the O-benzyl- and the O-thexyl-
dimethylsilyl protected ketones 9 and 10 in the presence
of RuCl2(PPh3)(Ph2P-Fc-oxaiPr) 5 afforded chiral alcohols
12 and 13 in excellent yields and good enantiomeric puri-
ties. Additional fine-tuning of the reaction conditions is
currently in progress and should lead to increased catalyst
performance. Furthermore, since the enantioselectivity
tends to depend on the type of protecting group used, the
examination of different protecting groups might also be
promising.
Acknowledgments
We are grateful to Mr. B. Grobbel and Mr. M. Waiz for
their technical assistance and to Dr. F. Naud for valuable
discussion and conduction of the inhibition experiment
with 8-hydroxychinoline.
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3. Conclusion
In conclusion, we have demonstrated that the Ruthenium
POX catalyst system RuCl2(PPh3)(Ph2P-Fc-oxaiPr) 5 pro-
vides a valuable alternative to the Noyori catalyst
RuCl2[(S)-BINAP][(S)-DAIPEN] 4. Whereas the asymmet-
ric reduction with Noyori’s catalyst 4 can be performed
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