A stereoselective catalytic nitroaldol reaction as the key step in a strategy for the synthesis of the renin inhibitor aliskiren

Article abstract of DOI:10.1002/ejoc.201403659

Aliskiren is the first-in-class orally active direct renin inhibitor. It was approved in 2007 for the treatment of hypertension. We have designed a new strategy for the convergent synthesis of aliskiren that involves a catalytic stereoselective nitroaldol reaction as the key step. A new enantiopure nitroalkane (synthon A¹), prepared in only three steps from a commercially available enantiopure 2-(arylmethyl)-3-methyl butanol derivative, was successfully used in a copper-catalysed Henry reaction to give a nitrolactone intermediate in which the correct configuration for the final product was established at all four stereocentres. Nitro-group reduction, Boc-protection of the resulting amine, aminolysis of the lactone with 3-amino-2,2-dimethylpropionamide, and finally Boc-deprotection led to the enantiopure renin inhibitor aliskiren.

Full text of DOI:10.1002/ejoc.201403659

FULL PAPER
DOI: 10.1002/ejoc.201403659
A Stereoselective Catalytic Nitroaldol Reaction as the Key Step in a Strategy
for the Synthesis of the Renin Inhibitor Aliskiren
Sergio Rossi,[a] Maurizio Benaglia,*[a] Riccardo Porta,[a] Livius Cotarca,*[b]
Paolo Maragni,[b] and Massimo Verzini[b]
Keywords: Drug design / Synthetic methods / Asymmetric synthesis / Diastereoselectivity / Medicinal chemistry / Nitro
compounds / Henry reaction
Aliskiren is the first-in-class orally active direct renin inhibi-
tor. It was approved in 2007 for the treatment of hyperten-
lysed Henry reaction to give a nitrolactone intermediate in
which the correct configuration for the final product was
sion. We have designed a new strategy for the convergent established at all four stereocentres. Nitro-group reduction,
synthesis of aliskiren that involves a catalytic stereoselective
nitroaldol reaction as the key step. A new enantiopure nitro-
alkane (synthon A1), prepared in only three steps from a
commercially available enantiopure 2-(arylmethyl)-3-methyl
butanol derivative, was successfully used in a copper-cata-
Boc-protection of the resulting amine, aminolysis of the lact-
one with 3-amino-2,2-dimethylpropionamide, and finally
Boc-deprotection led to the enantiopure renin inhibitor
aliskiren.
During the whole development program, the synthesis
of aliskiren remained a central problem, together with the
development of a commercially viable manufacturing pro-
cess. When we began our investigation, a long list of papers
was available in both the open[4] and the patent literature[5]
describing the work carried out at the above-mentioned
companies in charge of the development work to progress
the drug candidate from discovery to marketing. Further
research groups mainly from academia have published their
contributions to achieving an original synthetic approach
to aliskiren.[6]
Introduction
Hypertension is estimated to afflict a billion individuals
worldwide, and is a major risk factor for stroke, coronary
artery disease, heart failure, and end-stage renal disease.[1]
The discovery of renin-angiotensin system (RAS) as a key
physiological regulator of blood pressure (BP) and fluid
homeostasis has provided numerous targets for pharmaco-
logical intervention.[2] The first and rate-limiting step of this
cascade is catalysed by the highly specific aspartic protease,
renin. The direct blocking of this step has long been recog-
nized as a promising new type of treatment for high blood
pressure (BP).
Aliskiren is the first-in-class orally active direct renin in-
hibitor. It received US Food and Drug Administration
(FDA) and European Medicines Agency (EMEA) approval
in 2007 for the treatment of hypertension, and it is currently
marketed in the United States as Tekturna®, and world-
wide as Rasilez®.[3] The marketing approval of aliskiren
was the result of a huge discovery and development effort
carried out at Novartis/Ciba–Geigy (lead identification and
optimization), Speedel (Phase I and II clinical develop-
ment), and finally again at Novartis, who licensed back the
compound in 2002 for Phase III clinical development, fol-
lowed by registration and marketing.
Results and Discussion
After reviewing several of the approaches reported in the
literature, some references suggested us that one possible
way to produce aliskiren at an acceptable cost was through
a convergent synthesis based on a synthon approach (Fig-
ure 1).[3a]
The three building blocks (synthons A, B, and C) could
be synthesized separately.[7,3a,5] Further steps in the final
linear synthetic sequence to aliskiren would involve three
key reactions: i) a nickel-catalysed cross-coupling reaction
of synthon A and synthon B; ii) a highly diastereoselective
halolactonization to build up the remaining stereogenic
centres under the influence of the two already existing
stereocentres; iii) aminolysis of the lactone to install syn-
thon C into the final molecular structure of aliskiren.
Based on this idea of a synthon approach, we designed
a new strategy for a convergent synthesis of the target mol-
ecule involving a catalytic stereoselective nitroaldol reaction
[a] Dipartimento di Chimica, Università degli Studi di Milano,
Via Golgi 19, 20133 Milano, Italy
E-mail: Maurizio.benaglia@unimi.it
http://users.unimi.it/Benagliagroup/
[b] ZaCh System SpA,
Via Dovaro, 2, 36045 Lonigo (VI), Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403659.
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S. Rossi, M. Benaglia, R. Porta, L. Cotarca, P. Maragni, M. Verzini
FULL PAPER
aldehyde, synthon B1.[10] In that key step, two new stereo-
centres would be formed in a stereochemically controlled
manner to give the key intermediate nitrolactone derivative.
Nitro-group reduction, followed by Boc-protection (Boc =
tert-butoxycarbonyl) of the amine would lead to the known
intermediate N-Boc lactone.[11] That compound would then
react with synthon C, 3-amino-2,2-dimethylpropionamide,
to give, after Boc removal, the target molecule, aliskiren.
The preparation of the enantiopure key intermediate be-
gan with the oxidation of (R)-2-[4-methoxy-3-(3-meth-
oxypropoxy)benzyl]-3-methylbutan-1-ol (1)[9] with oxalyl
chloride and DMSO to give aldehyde 2 in almost quantita-
tive yield (Scheme 2). Reaction of 2 with ammonium acet-
ate and nitromethane directly gave nitroalkene 3, which was
reduced with sodium borohydride to give the desired
enantiopure nitro derivative (i.e., 4).
Figure 1. Previously reported synthon approach to produce the
renin inhibitor aliskiren.[3a]
as the key step (Figure 2). Two new building blocks, syn-
thon A1 and synthon B1, would be synthesized, and then
coupled through a catalytic stereoselective Henry reaction.
Finally, synthon C would be installed by a lactone-aminoly-
sis reaction to give enantiopure aliskiren.[8]
Figure 2. This work: convergent synthesis of aliskiren based on a
new synthon approach.
The planned synthetic sequence is shown in Scheme 1.
First, synthon A1 would be synthesized in just three steps
from commercially available enantiopure alcohol 1.[9]
Enantiopure synthon A1 would then be subjected to a cop-
Scheme 2. Synthesis of enantiopure nitroalkane 4 (synthon A1) and
per-catalysed diastereoselective nitroaldol reaction with the catalytic nitroaldol reaction.
Scheme 1. A new synthetic plan for the synthesis of the renin inhibitor aliskiren.
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Synthesis of the Renin Inhibitor Aliskiren
The crucial step used to couple synthons A1 and B1 was Table 1. Catalytic stereoselective nitroaldol reaction between nitro-
alkane 4 and aldehyde 5.[a]
a syn-selective nitroaldol catalytic reaction.[12] Recently,
catalytic stereoselective Henry reactions have been the sub-
ject of intensive research.[13] However, most of the reported
reactions involved nitromethane, or, in only a few cases,
very simple aliphatic nitroalkanes. Methods based on or-
ganocatalysis[14] and on organometallic catalysis[15] have
been reported, and an excess of the nitroalkane (usually 5–
10 equiv.) was used in all cases. An extensive preliminary
investigation of the reaction between 4 and 5 showed that
noncatalytic methods involving achiral stoichiometric pro-
moters or achiral catalysts were not effective in controlling
the stereochemical outcome of the reaction.
Therefore we focussed our attention on the use of chiral
catalytic species. We decided to concentrate on a relatively
inexpensive and readily available chiral copper(II) com-
plex,[16] generated in situ by mixing copper diacetate and a
chiral 1,2-diamine derivative.[17]
Entry Catalyst Nitro alk. Temp.
Yield[b] dr
[%]
loading
equiv.
[°C]
7a/7b/7c/7d[c,d]
1
2
3
4
10%
10%
10%
20%
5%
1
2
3
1
5 °C
5 °C
5 °C
5 °C
5 °C
0 °C
5 °C
15 °C
5 °C
30
65
91
41
85
47
91
87
43
n.d.
0:20:5:75
2:16:4:78
n.d.
5:20:10:65
7:12:5:76
0:18:2:80
9:18:12:61
n.d.
5
3
6
10%
10%
10%
10%
3
7
2.3
2.3
2.3
8
9[e]
[a] Reaction conditions: aldehyde 5 (1 equiv.) was added to a THF
solution of catalyst, DIPEA (0.1 equiv.) and 4. Reaction time: 48 h.
[b] Isolated yields after chromatographic purification. [c] Dia-
stereomeric ratio determined from the NMR spectrum of the crude
reaction mixture, and confirmed after purification. [d] Diastereo-
isomeric ratio determined on nitrolactone 7; n.d.: not determined.
[e] Reaction time: 24 h.
In a typical procedure, nitroalkane 4 was added to a
THF solution of the chiral copper complex and DIPEA yield but a lower diastereoselectivity. The conditions of
(diisopropylethylamine) at 5 °C. After a few minutes, alde- Table 1, entry 7 were identified as the best compromise,[20]
hyde 5 was introduced, and the reaction mixture was stirred giving the product in 91% yield and with 80% selectivity
for 48 h. A quick chromatographic purification gave ni- for the correct isomer.[21]
troaldol product 6 as an inseparable mixture of isomers.
Nitroaldol product 6 was easily separated from unreacted responding amine (i.e., 8). The amine was purified as its
nitroalkane 4, which was recovered quantitatively. Boc derivative 9, and the correct absolute stereochemistry
Enantiopure nitrolactone 7d was then reduced to the cor-
Treatment of 6 with a catalytic amount of PTSA (p-tolu- of the product was confirmed by comparison of the analyti-
enesulfonic acid) led to the formation of nitrolactone 7. The cal data of synthetic 9 with those reported in the litera-
major isomer, 7d, with the correct configuration at all four ture.[6]
stereocentres, could be isolated as in enantiopure form by
The nitro-group reduction was carried out using a new
flash chromatography.[18] We varied several parameters metal-free method involving trichlorosilane and a tertiary
while looking for the best conditions for this reaction. Se- amine. This is a very mild procedure, and it did not affect
lected results from these optimization studies are shown in the stereochemical integrity of the four stereocentres of the
Table 1.[19]
molecule.[22] Amine 8 was isolated in 99% yield, and pro-
At least 2 equiv. of nitroalkane 4 were necessary to guar- tected as Boc derivative 9 in 98% yield (Scheme 3).
antee a good yield. Lowering the reaction temperature from Finally, N-Boc-lactone 9 was treated with 3-amino-
5 °C to 0 °C did not have any appreciable influence on the 2,2-dimethylpropionamide (10) to give N-Boc-protected
stereoselectivity, but resulted in a significantly lower yield. aliskiren 11 in 77% yield after purification of chromatog-
Increasing the reaction temperature to 15 °C, led to a good raphy. The NMR spectrum of the Boc-aliskiren prepared
Scheme 3. Final steps in the synthesis of enantiopure renin inhibitor aliskiren; MTBE = methyl tert-butyl ether.
Eur. J. Org. Chem. 2015, 2531–2537
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S. Rossi, M. Benaglia, R. Porta, L. Cotarca, P. Maragni, M. Verzini
FULL PAPER
Methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutan-1-ol (1) and
methyl (S)-2-isopropyl-4-oxobutanoate (5) were prepared accord-
ing to literature procedures (see main text for references).
by this approach was identical to the NMR spectrum of a
sample of Boc-aliskiren prepared starting from commer-
cially available aliskiren hemifumarate (see Supporting In-
formation for NMR spectra and HPLC analysis).[23] Depro-
tection of N-Boc-protected aliskiren 11 gave the enantio-
Synthesis of Compound 2: Compound 2 is known,[24] and it was
prepared starting from the commercially available alcohol (R)-2-[4-
pure final product, aliskiren (see Supporting Information methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutan-1-ol (1). A
solution of oxalyl chloride (18.9 mmol, 2.8 equiv., 1.62 mL) in dry
dichloromethane (18 mL) was prepared under a nitrogen atmo-
sphere at –78 °C. This solution was stirred for 10 min, and then
dry dimethyl sulfoxide (3 mL, 6.2 equiv.) was rapidly added. The
solution was stirred for 20 min at –78 °C, then a solution of chiral
alcohol 1 (6.8 mmol, 1.0 equiv., 2.02 g) in dry dichloromethane
(6 mL) was added. After 1 h, dry triethylamine (43.5 mmol,
6.4 equiv., 6 mL) was added, and then the solution was warmed to
0 °C and stirred for 1 h. After this time, saturated aqueous ammo-
nium chloride (30 mL) and dichloromethane (30 mL) were added
at 0 °C, then the organic layer was separated. The aqueous phase
was extracted twice with dichloromethane (30 mL), then the com-
bined organic layers were washed with brine, dried with anhydrous
for NMR spectroscopic data and HRMS analysis of the
final product).
Conclusions
In conclusion, a new and straightforward synthesis of the
renin inhibitor aliskiren has been successfully ac-
complished. The convergent synthetic approach allowed us
to prepare enantiopure Boc-aliskiren in only eight steps and
39% overall yield. In this innovative approach, two new
stereocentres are established through a copper-catalysed
nitroaldol reaction between two enantiopure synthons,
namely (S)-3-isopropyl-4-[3-(3-methoxypropoxy)-4-meth-
sodium sulfate, and concentrated under vacuum to give
2
(6.5 mmol, 1.91 g, 95%) as a yellowish oil, which was used without
oxy]phenyl-1-nitro-pentane and (S)-methyl-2-isopropyl-4- further purification. Rf = 0.67 (hexane/EtOAc, 7:3). 1H NMR data
are consistent with literature data.[24] 1H NMR (300 MHz, CDCl3):
oxobutanoate. After the correct configuration at all four of
the stereocentres of the final product had been established,
the reaction sequence involved reduction of the nitro group
to an amine, which was achieved through an innovative
metal-free method that was shown to respect the stereo-
chemical integrity of the molecule. This work may open new
possibilities for the preparation of a wide variety of
enantiopure 1,2-amino alcohol derivatives of pharmaceuti-
cal interest.
δ = 9.70 (s, 1 H, CHO), 6.69–6.80 (m, 3 H, aryl), 4.11 (t, J = 6.5 Hz,
2 H, CH2OAr), 3.84 (s, 3 H, CH3OAr), 3.59 (t, J = 6.2 Hz, 2 H,
CH3OCH2), 3.38 (s, 3 H, CH3OCH2), 3.10 (q, J = 7.4 Hz, 1 H,
CHCHO), 2.94 (dd, J = 9.2, J = 16.9 Hz, 1 H, ArCH2), 2.72 (dd,
J = 4.7, J = 14.3 Hz, 1 H, ArCH2), 2.47–2.51 [m, 1 H, CH(CH3)
2], 2.09–2.13 (m, 2 H, CH3OCH2CH2), 1.06 [d, J = 3.3 Hz, 3 H,
CH(CH3)2], 1.04 [d, J = 3.3 Hz, 3 H, CH(CH3)2] ppm. 13C NMR
(75 MHz, CDCl3): δ = 205.06, 148.40, 147.93, 132.15, 121.04,
114.19, 111.93, 69.28, 66.04, 59.70, 58.59, 56.00, 31.83, 29.56,
28.28, 19.90, 19.73 ppm.
Synthesis of Compound 3: Compound 2 (6.5 mmol, 1.0 equiv.,
1.91 g) was dissolved in nitromethane (46 mL), and NH4OAc
(7.2 mmol, 1.1 equiv., 555 mg) was added. The mixture was heated
at reflux for 24 h, then the solvent was evaporated under vacuum.
H2O/CH2Cl2 (1:1; 40 mL) was added, and the organic layer was
separated. The aqueous phase was extracted twice with dichloro-
methane (20 mL), then the combined organic layers were washed
with brine, and dried with anhydrous sodium sulfate. The solvent
was removed under vacuum to give 3 (5.9 mmol, 2.13 g, 91%) as a
brownish oil, which was used without further purification. Rf =
Experimental Section
General Methods: Dry solvents were purchased and stored under
nitrogen over molecular sieves (bottles with crown caps). Reactions
were monitored by analytical thin-layer chromatography (TLC)
using silica gel 60 F 254 precoated glass plates (0.25 mm thickness),
which were visualized using UV light. Flash chromatography was
carried out on silica gel (230–400 mesh). 1H NMR spectra were
recorded on spectrometers operating at 300 MHz (Bruker Fourier
300 or AMX 300). 1H chemical shifts are reported in ppm (δ) rela-
tive to tetramethylsilane, and residual solvent was used as the in-
ternal standard (CDCl3 δ = 7.26 ppm). 13C NMR spectra were re-
corded on 300 MHz spectrometers (Bruker Fourier 300 or AMX
300) operating at 75 MHz with complete proton decoupling. 13C
chemical shifts are reported in ppm (δ) relative to tetramethylsilane,
and the respective solvent resonance was used as the internal stan-
1
0.43 (hexane/EtOAc, 7:3, stained yellow with KMnO4). H NMR
(300 MHz, CDCl3): δ = 7.10–7.18 (dd, J = 9, J = 12 Hz, 1 H,
CH2=CH2NO2), 6.62–6.80 (m, 4 H, aryl-H, CH2=CH2NO2), 4.07–
4.11 (m, 2 H, CH2OAr), 3.84 (s, 3 H, CH3OAr), 3.59 (m, 2 H,
CH3OCH2), 3.38 (s, 3 H, CH3OCH2), 2.87 (dd, J = 3, J = 12 Hz,
1 H, ArCH2), 2.58 (dd, J = 9, J = 12 Hz, 1 H, ArCH2), 2.31–2.38
[m, 1 H, CH(CH3)2], 2.08–2.13 (m, 2 H, CH3OCH2CH2), 1.86–1.91
[m, 1 H, CH(CH3)2], 1.02 [d, J = 6 Hz, 3 H, CH(CH3)2], 0.98 [d,
J = 6 Hz, 3 H, CH(CH3)2] ppm. 13C NMR (75 MHz, CDCl3): δ =
148.36, 148.06, 143.84, 139.98, 131.44, 121.20, 114.17, 111.88,
69.25, 66.12, 58.55, 55.93, 47.84, 37.65, 31.10, 29.53, 20.79,
18.63 ppm. HRMS (ESI+): calcd. for C18H27N1O5Na+ 360.17814;
found 360.17827. [α]2D2 = +5.0 (c = 0.28, CHCl3).
dard (CDCl3,
δ = 77.0 ppm). High-resolution mass spectra
(HRMS) were recorded at CIGA (Centro Interdipartimentale
Grandi Apparecchiature, Milano), with an APEX II mass spec-
trometer and Xmass software (Bruker Daltonics). Electrospray ion-
ization mass spectra MS (ESI) were recorded as methanol solutions
using a AB Sciex Instruments triple quadrupole LC/MS/MS API
365 mass spectrometer. Optical rotations were measured with a Per-
kin–Elmer 241 polarimeter at 589 nm using a 5 mL cell with a path
length of 1 dm. HPLC purity analysis was performed under the
conditions reported below with an Agilent 1200 series instrument.
Synthesis of Compound 4: Compound 3 (5.9 mmol, 1.0 equiv.,
2.13 g) was dissolved in ethanol (15 mL), and the solution was
cooled to –20 °C. After 10 min, sodium borohydride (11.8 mmol,
2 equiv., 446 mg) was slowly added, and the mixture was stirred for
1 h at –20 °C. After this time, glacial acetic acid (2 mL) was added,
and the solution was warmed to room temperature and diluted
Materials: Commercial-grade reagents and solvents were used
without further purification. 3-Amino-2,2-dimethylpropionamide
(10) was purchased and used without further purification. (R)-2-[4-
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Synthesis of the Renin Inhibitor Aliskiren
with water (10 mL) and ethyl acetate (20 mL). The organic layer
was separated, and the aqueous phase was extracted three times
with ethyl acetate (15 mL). The combined organic layers were
washed with brine, and dried with anhydrous sodium sulfate. The
solvent was removed under vacuum, and the crude product was
purified by flash column chromatography on silica gel (hexane/
with water (10 mL), dried with anhydrous sodium sulfate, and then
concentrated under reduced pressure. The crude product was puri-
fied by flash column chromatography on silica gel (CH2Cl2/MeOH,
8:2) to give pure L* (1.05 mmol, 3.86 mg, 48%) as an off-white
solid. H NMR (300 MHz, CDCl3): δ = 8.54 (d, J = 5.6 Hz, 2 H,
pyridyl-H), 7.29 (d, J = 4.8 Hz, 2 H, pyridyl-H), 7.22 (d, J = 6.8 Hz,
1
EtOAc, 9:1 to 7:3) to give 4 (5.6 mmol, 2.03 g, 95%) as a yellow 1 H, phenyl-H), 6.89 (d, J = 7.2 Hz, 1 H, phenyl-H), 6.77–6.72 (m,
liquid. Rf = 0.41 (hexane/EtOAc, 8:2, stained yellow with KMnO4).
1H NMR (300 MHz, CDCl3): δ = 6.81 (d, J = 6 Hz, 1 H, aryl),
6.68–6.71 (m, 2 H, aryl), 4.21 (t, J = 6 Hz, 2 H, CH2NO2), 4.12 (t,
1 H, phenyl-H), 4.15–4.08 (m, 1 H, CH2NH), 3.95 (d, J = 14.4 Hz,
1 H, CH2NH), 3.84 (d, J = 13.2 Hz, 1 H, CH2NH), 3.73 (d, J =
14.4 Hz, 1 H, CH2NH), 2.34–2.22 (m, 4 H, 2 NH, 2 cyclohexyl-
J = 6 Hz, 2 H, CH2OAr), 3.86 (s, 3 H, CH3OAr), 3.60 (t, J = 6 Hz, H), 1.75 (br., 2 H, cyclohexyl-H), 1.45 (s, 9 H, CH3), 1.26–0.99 (m,
2 H, CH3OCH2), 3.38 (s, 3 H, CH3OCH2), 2.68 (dd, J = 6, J = 6 H, cyclohexyl-H) ppm.
12 Hz, 1 H, ArCH2), 2.35 (dd, J = 6, J = 12 Hz, 1 H, ArCH2), 2.12
Synthesis of Compound 7: Compound 6 (0.79 mmol, 1.0 equiv.,
(m, 2 H, CH3OCH2CH2), 1.86–1.90 [m, 1 H, CH(CH3)2], 1.75–1.86
393 mg) was dissolved in dry toluene (6 mL), and molecular sieves
(m, 1 H, CH2CH2NO2), 1.59–1.75 (m, 1 H, CH2CH2NO2), 0.95 [d,
(4 Å) and p-toluenesulfonic acid (PTSA; 0.08 mmol, 0.1 equiv.,
J = 6 Hz, 3 H, CH(CH3)2], 0.91 [d, J = 6 Hz, 3 H, CH(CH3)2]
14 mg) were added. The mixture was stirred at reflux for 18 h. After
ppm. 13C NMR (75 MHz, CDCl3): δ = 148.46, 147.92, 133.00,
this time, the solvent was removed under reduced pressure to give
compound 7 (0.78 mmol, 381 mg, 99%) as a mixture of four dia-
stereoisomers. TLC (hexane/EtOAc, 7:3, stained blue with phos-
phomolybdic acid): Rf1 = 0.28, Rf2 = 0.24, Rf3 = 0.21, Rf4 = 0.16.
121.11, 114.12, 111.93, 74.48, 69.22, 66.04, 58.44, 55.89, 43.09,
36.57, 29.59, 29.30, 28.27, 18.86, 18.37 ppm. HRMS (ESI+): calcd.
for C18H29N1O5Na+ 362.19379; found 362.19378. [α]2D2 = +1.5 (c =
0.40, CHCl3).
Flash column chromatography on silica gel (hexane/EtOAc, 9:1)
General Procedure for the Nitroaldol Reaction: Cu(OAc)2 gave pure diastereoisomer 7d (0.62 mmol, 303 mg, 80%) as an off-
(0.087 mmol, 0.1 equiv., 16 mg) and chiral ligand L* (0.087 mmol,
0.1 equiv.) were dissolved in dry THF (1 mL) under a nitrogen at-
mosphere, and the solution was stirred for 30 min. Then, diisoprop-
ylethylamine (DIPEA; 0.087 mmol, 0.1 equiv., 15 μL) was added,
and the solution was cooled to 0 °C. After 10 min, compound 4
(2.0 mmol, 2.3 equiv., 724 mg) and a solution of chiral aldehyde 5
(0.87 mmol, 1.0 equiv., 138 mg) in dry THF (1.8 mL) were added.
The mixture was stirred at temperature and for the time indicated
in Table S1 under a nitrogen atmosphere. After this time, the sol-
vent was removed under vacuum, and the crude mixture was fil-
tered through a pad of silica gel (diameter = 2 cm, h = 5 cm, hex-
white solid. The absolute configuration was determined by com-
parison with literature data after conversion of 7d into 9, a known
compound.[25]
Data for 7d: Rf = 0.16 (hexane/EtOAc, 7:3, stained blue with phos-
1
phomolybdic acid). H NMR (300 MHz, CDCl3): δ = 6.82 (d, J =
9 Hz, 1 H, aryl), 6.69–6.75 (m, 2 H, aryl), 4.56–4.64 (td, J = 6, J
= 9 Hz, 1 H, NO2CHCHO), 4.13 (t, J = 6 Hz, 3 H, CH2OAr),
4.09–4.12 (m, 1 H, CHNO2), 3.86 (s, 3 H, CH3OAr), 3.60 (t, J =
6 Hz, 2 H, CH3OCH2), 3.38 (s, 3 H, CH3OCH2), 2.62–2.69 (part
A of an AB system, dd, J = 6, J = 9 Hz, 1 H, ArCH2), 2.42–2.50
(part A of an AB system, dd, J = 6, J = 9 Hz, 1 H, ArCH2),
2.32–2.40 (m, 1 H, CH2CHNO2), 2.04–2.18 (m, 4 H, CH2CHNO2,
ane/EtOAc, 8:2). Unreacted chiral nitroalkane
4 (1.1 mmol,
398 mg) was recovered. Product 6 (0.79 mmol, 393 mg) was ob-
tained as a mixture of four diastereoisomers, and this mixture was
used in the next step without further purification. Rf = 0.18 (hex-
ane/EtOAc, 7:3, stained yellow with KMnO4).
CH3OCH2CH2, CH2CHO), 1.61–1.83 [m,
2 H, CH2CHO,
COCHCH(CH3)2], 1.40–1.62 (m, 2 H, ArCH2CH, ArCH2CHCH),
1.03 [d, J = 9 Hz, 3 H, COCHCH(CH3)2], 0.94 [d, J = 6 Hz, 3 H,
COCHCH(CH3)2], 0.90 [d, J = 6 Hz, 3 H, CH(CH3)2], 0.87 [d, J
= 6 Hz, 3 H, CH(CH3)2] ppm. 13C NMR (75 MHz, CDCl3): δ =
176.37, 148.72, 148.19, 132.47, 121.17, 114.31, 111.91, 90.02, 69.35,
Synthesis of Chiral Ligand (L*): Chiral ligand L* was synthesized
according to a literature procedure.[17] (1R,2R)-(–)-1,2-Diamino-
cyclohexane (2.19 mmol, 1.0 equiv., 250 mg) was dissolved in dry 66.21, 58.68, 56.14, 44.63, 42.10, 37.84, 30.74, 30.10, 29.61, 28.97,
dichloromethane (20 mL), and a solution of pyridine-4-carb-
aldehyde (2.19 mmol, 1.0 equiv., 206 μL) in dry dichloromethane
(7 mL) was added very slowly over a period of 30 min. The re-
sulting mixture was stirred at room temperature for 1 h. Then a
solution of 3-tert-butyl-2-hydroxybenzaldehyde (2.19 mmol,
1.0 equiv., 375 μL) in dichloromethane (7 mL) was added dropwise.
The resulting mixture was heated to reflux for 2 h, then it was
cooled to room temperature, and stirring was continued overnight.
The solvent was removed under reduced pressure to give a crude
yellow oil, which was passed through a short silica gel column (hex-
ane/EtOAc, 3:1, with 3% methanol, Rf = 0.12) to give the pure
intermediate (62%) as a sticky yellow oil.
26.33, 20.19, 19.51, 18.54, 17.55 ppm. HRMS (ESI+): calcd. for
C25H39N1O7Na+ 488.26187; found 488.26150. [α]2D2 = +13.3 (c =
0.40, CHCl3).
Synthesis of Compound 8: Compound 7d was converted into the
corresponding primary amine (i.e., 8) according to a patent pro-
cedure.[22] Compound 7d (0.62 mmol, 1.0 equiv., 303 mg) was dis-
solved in dry dichloromethane (5 mL) under a nitrogen atmo-
sphere, and then DIPEA (3.1 mmol, 5.0 equiv., 540 μL) was added.
The mixture was cooled to 0 °C, and after 10 min, freshly distilled
trichlorosilane (1.86 mmol, 3.0 equiv., 188 μL) was added slowly.
The mixture was warmed to room temperature, and was stirred for
5 h. The reaction was monitored by TLC, and when all the starting
material had been consumed, the mixture was quenched with
This oil was dissolved in absolute MeOH (20 mL), then solid
NaBH4 (11 mmol, 5.0 equiv., 416 mg) was added in small portions NaHCO3 (saturated aq.; 3 mL), and the aqueous layer was ex-
at 0 °C over a period of 1 h. The mixture was stirred at room tem-
perature for 18 h, then it was diluted with water (50 mL), treated
with HCl (5% aq.) until pH = 2.0, then extracted twice with di-
chloromethane (50 mL) to remove some of the impurities. The
tracted twice with dichloromethane (5 mL). The combined organic
layers were washed with brine, and dried with anhydrous Na2SO4.
The solvent was removed under vacuum to give compound 8
(0.61 mmol, 266 mg, 99%) as a white solid. The product was used
aqueous phase was treated with NH4OH (33 wt.-% solution; in the next synthetic step without further purification. Rf = 0.06
1
10 mL) until pH ≈ 10, then the solution was then extracted twice
with CH2Cl2 (30 mL). The combined organic layers were washed
(CH2Cl2/MeOH, 6:4). H NMR data are consistent with literature
data.[25c] 1H NMR (300 MHz, CDCl3): δ = 6.65–6.7 (m, 3 H, aryl),
Eur. J. Org. Chem. 2015, 2531–2537
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2535

S. Rossi, M. Benaglia, R. Porta, L. Cotarca, P. Maragni, M. Verzini
Description of catalytic experiments. NMR spectra and HPLC
FULL PAPER
4.09–4.11 (m, 1 H, NH2CHCHO, and t, J = 6 Hz, 2 H, CH2OAr),
3.80 (s, 3 H, CH3OAr), 3.55 (t, J = 6 Hz, 2 H, CH3OCH2), 3.33 (s, traces of the products.
3 H, CH3OCH2), 2.43–2.65 (m, 3 H), 1.93–2.10 (m, 4 H), 1.60–
1.73 (m, 2 H), 1.23–1.39 (m, 2 H), 1.14–1.28 (m, 2 H), 0.98 (d, J
= 6 Hz, 3 H), 0.94 (d, J = 6 Hz, 3 H), 0.84–0.89 (m, 6 H) ppm.
Acknowledgments
Synthesis of Compound 9: Compound 8 (0.68 mmol, 1.0 equiv.,
M. B. thanks the European Union, COST action CM9505
296 mg) was dissolved in methanol (5 mL), and Boc anhydride
(1.36 mmol, 2.0 equiv., 297 mg) was added. The mixture was al-
lowed to stir at room temperature for 24 h. After this time, ethyl
acetate (10 mL) and brine (3 mL) were added. The organic layer
was separated, and the organic phase was extracted three times
with EtOAc (8 mL). The combined organic layers were dried with
anhydrous Na2SO4, and the solvent was removed under vacuum.
The crude mixture was purified by flash column chromatography
on silica gel (eluent CH2Cl2/EtOAc, 95:5) to give compound 9
(0.67 mmol, 374 mg, 98%) as a white solid. Rf = 0.76 (CH2Cl2/
MeOH, 95:5). 1H NMR and 13C NMR data are consistent with
literature data.[25c] 1H NMR (300 MHz, CDCl3): δ = 6.69–6.80 (m,
3 H, aryl), 4.38–4.41 (m, 2 H, NHBocCHCHO, NHBocCHCHO),
4.11 (t, J = 9 Hz, 2 H, CH2OAr), 3.85 (s, 3 H, CH3OAr), 3.81–3.84
(m, 1 H, CHNHBoc), 3.59 (t, J = 9 Hz, 2 H, CH3OCH2), 3.37 (s,
3 H, CH3OCH2), 2.50–2.63 (m, 2 H), 2.30–2.48 (dd, J = 6, J =
9 Hz, 1 H), 2.00–2.25 (m, 3 H), 1.50–1.75 (m, 3 H), 1.48 (s, 9 H,
Boc), 1.25–1.48 (m, 3 H), 1.02 (d, J = 6 Hz, 3 H), 0.95 (d, J =
6 Hz, 3 H), 0.84 (d, J = 6 Hz, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 179.2, 156.4, 148.4, 147.8, 133.9, 121.5, 114.5, 111.9,
81.6, 79.9, 69.6, 66.2, 58.8, 56.2, 52.1, 46.0, 42.6, 37.6, 33.5, 29.8,
29.4, 28.5 (3 C), 27.9, 26.8, 20.6, 20.5, 18.6, 16.7 ppm. MS (ESI+):
calcd. for C30H49N1O7Na+ 558.45; found 558.4.
“ORCA” Organocatalysis, Università degli Studi di Milano, and
ZaCh System SpA (Zambon Chemicals) for financial support. Also
we would like to thank Mrs. S. Blanchet and Mrs. M. Maruani
(ZaCh System SpA) for the preparation of aldehyde 5, and Mr.
Mauro Ghisetti and Mr. Francesco Revello for early stage experi-
ments.
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For some recent work towards the synthesis of aliskiren, see
Synthesis of Compound 11: Compound 9 (0.67 mmol, 1.0 equiv.,
374 mg) was dissolved in MTBE (5 mL), and then 2-hydroxypyr-
idine (0.8 mmol, 1.2 equiv., 76 mg), triethylamine (0.8 mmol,
1.2 equiv., 111 μL), and amine 10 (1.0 mmol, 1.5 equiv., 116 mg)
were added. The mixture was stirred at 80 °C for 48 h. After this
time, the crude mixture was diluted with toluene (5 mL), and the
organic layer was washed with NaHSO4 (10 wt.-% aq.; 5 mL). The
aqueous phase was extracted four times with toluene (8 mL). The
combined organic layers were washed with brine, and dried with
anhydrous Na2SO4. The solvent was removed under vacuum to give
a yellowish oil. Hexane (5 mL) was added to this oil, and the crude
product was isolated as an off-white solid. This solid was purified
by flash column chromatography on silica gel (CH2Cl2/MeOH,
95:5) to give the desired N-Boc-aliskiren 11 (0.52 mmol, 351 mg,
1
77%) as a white solid. Rf = 0.31 (CH2Cl2/MeOH, 99:1). H NMR
also: G. Nam, S. Y. Ko, Helv. Chim. Acta 2012, 95, 1937–1945;
and 13C NMR data are consistent with literature data.[25d] 1H
NMR (300 MHz, CDCl3): δ = 6.60–6.79 (m, 3 H, aryl), 6.50 (br.
s, 1 H), 6.19 (br. s, 1 H), 5.69 (br. s, 1 H), 4.71 (br. d, 1 H), 4.12
(t, J = 6 Hz, 2 H, CH2OAr), 3.84 (s, 3 H, CH3OAr), 3.59 (t, J =
6 Hz, 2 H, CH3OCH2), 3.45–3.57 (m, 2 H), 3.47 (s, 3 H,
CH3OCH2), 3.28–3.46 (m, 1 H), 2.63 (dd, J = 6, J = 9 Hz, 2 H),
2.42 (dd, J = 6, J = 9 Hz, 1 H), 2.06–2.12 (m, 3 H), 1.78–1.94 (m,
1 H), 1.50–1.78 (m, 5 H), 1.48 (s, 9 H, Boc), 1.24 (s, 6 H), 0.93 (d,
J = 6 Hz, 6 H), 0.84 (d, J = 6, J = 9 Hz, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 180.3, 176.6, 156.7, 148.3, 147.6, 134.5,
121.5, 114.6, 111.7, 79.2, 71.1, 69.6, 66.1, 58.8, 56.2, 54.0, 51.4,
47.4, 43.2, 42.4, 37.5, 34.1, 32.2, 29.9, 29.7, 28.6, 28.1, 24.3, 21.4,
ˇ
g) F. Pozgan, B. Stefane, D. Kieemet, J. Smodisˇ, R. Zupet,
ˇ
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[7] J. Engel, A. Kleemann, B. Kutscher, D. Reichert, Pharmaceuti-
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[8] P. Maragni, M. Benaglia, L. Cotarca, M. Verzini (ZaCh System
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[9] For the preparation of alcohol 1, see references 4a–4c in: F.
Wang, X. Y. Xu, F. Y. Wang, L. Peng, Y. Zhang, F. Tian, L. X.
Wang, Org. Process Res. Dev. 2013, 17, 1458–1462.
[10] Aldehyde 5 was synthesized by ozonolysis of commercially
available (S)-methyl-5-chloro-2-isopropyl-4-pentenoate. For ex-
perimental details, see ref.[8] Y. Zhang, L. Zhao, S. Lee, J. Y.
Ying, Adv. Synth. Catal. 2006, 348, 2027.
[11] For complete characterization of Boc-lactone 9, see ref.[6d]
[12] For a noncatalytic nitroaldol reaction, see: F. Zhang, Z. Chen,
P. Sun, WO 2011/127797, 2011.
+
21.4, 20.5, 16.9 ppm. MS (ESI+): calcd. for C35H61N3O8 652.45;
found 652.4.
Supporting Information (see footnote on the first page of this arti-
cle): Preparation, analysis, and characterization of intermediates.
[13] Reviews: a) M. Shibasaki, H. Groger, M. Kanai, in: Compre-
hensive Asymmetric Catalysis, Supplement 1 (Eds.: E. N. Ja-
2536
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 2531–2537

Synthesis of the Renin Inhibitor Aliskiren
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that was known to be syn-selective and to work under the ex-
perimental conditions in view of a possible preparation on a
larger scale.
As a control experiment, the nitroaldol reaction between 4 and
5 was carried out under the conditions of Table 1, entry 7 in
the presence of the enantiomeric catalyst, prepared from (S,S)-
1,2-diaminocyclohexane. We observed the formation of the
four isomers with a low stereoselectivity (ratio 21:25:23:31),
thus confirming the existence of a matched and a mismatched
pair between the catalyst and the chiral reagents.
For the complete characterization of the correct isomer of 7,
see the Supporting Information. The identification of the iso-
mer with the correct absolute configuration at all stereocentres
was determined by converting all of the isomers of 7 into the
corresponding Boc derivatives (i.e. 9), and comparing each of
these isomers with the known product Boc-lactone 9 (for fur-
ther details, see the Supporting Information).
The method is described in the patent: M. Bonsignore, M. Be-
naglia (Università degli Studi di Milano, Milano, Italy), PCT/
EP/2013/0683, 2013.
[20]
[21]
[22]
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[16] For the preparation of the chiral ligand, and experimental de-
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[17] See ref.[15a] and also: G. Zhang, E. Yashima, W. D. Woggon,
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[23] For complete characterization of the correct isomer of Boc-
aliskiren 11 and, for comparison, of the other three isomers
with undesired configurations, see the Supporting Information.
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[18] When the reaction was run on a scale of a few hundred milli-
grams, the major isomer (i.e. 7d) could be isolated pure. How-
ever, when the reaction was run on a gram scale, a fraction
of 7d was recovered as a mixture with another isomer. After
transformation into Boc-lactone 9, it was possible to purify
and isolate the correct enantiopure isomer by flash chromatog-
raphy.
[19] The focus of this work was not to explore a wide variety of
chiral catalysts, but to find the best conditions for the Henry
reaction between these two new, specific reaction partners, 4
and 5. Therefore, we just decided to select the copper catalyst
Received: December 20, 2014
Published Online: March 2, 2015
Eur. J. Org. Chem. 2015, 2531–2537
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2537