Formal total synthesis of aliskiren

Article abstract of DOI:10.1002/chem.201406523

The efficient and selective formal total synthesis of aliskiren is described. Aliskiren, a renin inhibitor drug, has received considerable attention, primarily because it is the first of the renin inhibitor drugs to be approved by the FDA. Herein, the formal synthesis of aliskiren by iridium-catalyzed asymmetric hydrogenation of two allylic alcohol fragments is reported. Screening a number of N,P-ligated iridium catalysts yielded two catalysts that gave the highest enantioselectivity in the hydrogenation, which gave the saturated alcohols in 97 and 93 % ee. In only four steps after hydrogenation, the fragments were combined by using the Julia-Kocienski reaction to produce late-stage intermediate in an overall yield of 18 %.

Full text of DOI:10.1002/chem.201406523

DOI: 10.1002/chem.201406523
Full Paper
&
Total Synthesis
Formal Total Synthesis of Aliskiren
Byron K. Peters, Jianguo Liu, Cristiana Margarita, and Pher G. Andersson*[a]
Abstract: The efficient and selective formal total synthesis of
aliskiren is described. Aliskiren, a renin inhibitor drug, has re-
ceived considerable attention, primarily because it is the first
of the renin inhibitor drugs to be approved by the FDA.
Herein, the formal synthesis of aliskiren by iridium-catalyzed
asymmetric hydrogenation of two allylic alcohol fragments is
reported. Screening a number of N,P-ligated iridium catalysts
yielded two catalysts that gave the highest enantioselectivity
in the hydrogenation, which gave the saturated alcohols in
97 and 93% ee. In only four steps after hydrogenation, the
fragments were combined by using the Julia–Kocienski reac-
tion to produce late-stage intermediate in an overall yield of
18%.
Introduction
Hypertension is the most modi-
fiable risk factor in the treat-
ment of heart disease. There-
fore, inhibition of kidney-pro-
duced renin has become an
emergent field of focus.[1] Aliski-
ren (Tekturna) is an efficient
renin-inhibitor drug used to
treat hypertension and renal
failure (Scheme 1). It is also the
first renin inhibitor to be admin-
Scheme 1. Retrosynthetic approach to key intermediate 1.
istered orally. Hence, a simple
and facile synthetic protocol for
its preparation is widely sought after. Several synthetic meth-
ods for its preparation have been reported[2] and some patent-
ed.[3]
lation of isovaleraldehyde using MacMillan’s catalyst.[2b,g] The
two fragments were joined by Yamaguchi esterification fol-
lowed by ring-closing metathesis to form a nine-membered
unsaturated lactone. Hanessian and ChØnard have also demon-
strated a palladium-catalyzed asymmetric allylation protocol to
prepare C-7. In this case, cross-metathesis was used to join the
two fragments to produce late-stage intermediate 1 with an
E:Z ratio of 86:14.[4b]
Aliskiren has four stereocenters: C-2, C-4, C-5, and C-7. Some
emphasis has been directed to the enantioselective prepara-
tion of C-2 and C-7.[4] In these syntheses, the chirality induced
at C-2 or C-7 or both has been utilized to direct stereoselectiv-
ity at C-4 and C-5. Thus, achieving high enantioselectivity at
these points is crucial to the total synthesis of aliskiren. In
a number of earlier reported syntheses, chiral auxiliaries (Evans’
oxazolidinones) have been used to prepare both C-2 and C-
7.[2a,c,d,4a] The two fragments are then joined by a Grignard reac-
tion or an aldol condensation.
Attention has also been focused on the preparation of C-7
through asymmetric hydrogenation. Excellent results for the
hydrogenation of the corresponding a,b-unsaturated esters
and acid have been achieved by using iridium, ruthenium and
rhodium, P,P-, and N,P-ligated catalysts.[5]
Organocatalysis has been employed by Hanessian and ChØ-
nard to prepare both C-2 and C-7 through an asymmetric ally-
Asymmetric methods for the preparation of analogues of C-
2 are scarce. Buchwald et al. have produced the corresponding
aldehyde by an asymmetric hydroformylation reaction with
92% ee in 91% yield.[6] Peterson et al. have prepared the alco-
hol by enantioselective Brønsted acid catalyzed kinetic resolu-
tion with 52% ee and 56% conversion. However, long reaction
times (72 h) were required.[7]
[a] B. K. Peters, J. Liu, C. Margarita, Prof. P. G. Andersson
Department of Organisk Kemi
Stockholm Universitet
Arrehniuslaboratoriet, 10691 Stockholm (Sweden)
E-mail: phera@organ.su.se
Iridium-catalyzed asymmetric hydrogenation is a valuable
tool for the hydrogenation of unfunctionalized and functional-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406523.
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ized olefins.[8] Andersson et al. have studied this reaction and
have not only expanded the substrate scope,[9] but also stud-
ied the mechanism and the origin of stereoselectivity.[10]
Here we report the formal synthesis of aliskiren through
a convergent approach employing the asymmetric hydrogena-
tion of two allylic alcohol fragments as key intermediates.
These fragments were combined by using the Julia–Kocienski
reaction to produce 1, a late-stage precursor in the preparation
of aliskiren.
This protocol allowed efficient preparation of 6 on a 23 g
scale.
Starting from 6, allylic alcohol 4 was prepared in two steps
by a protocol developed by Valenta et al.[12] First, compound 6
was epoxidized with mCPBA to give 7 in a 1:5 cis:trans ratio
(Scheme 2 iii). Next, base-catalyzed rearrangement with K2CO3
in refluxing ethanol afforded pure (E)-4 after workup (56%
yield).[13] A small amount of the corresponding unsaturated lac-
tone, presumably formed by spontaneous cyclization of any
(Z)-4 formed in the reaction, was also observed in the crude
reaction mixture. However, the volatile lactone was completely
removed during workup, which involved evaporation of sol-
vents.
Results and Discussion
The retrosynthetic analysis (Scheme 1) of aliskiren is shown in
Scheme 1; precursor 1 resulted in synthons 2 and 3. The fact
that chirality in these fragments could easily be installed by
using asymmetric hydrogenation made 4 and 5 synthetic tar-
gets.
Allylic alcohol 5 was prepared via bromide 8, previously ob-
tained by Maibaum et al. in four steps from isovanillin
(Scheme 3A).[14] Following a procedure established by Wulff
We originally planned to prepare allylic alcohol 4 from ethyl
crotonate by an alkylation, epoxidation, and rearrangement se-
quence (Scheme 2). The efficient and high-yielding preparation
Scheme 3. Preparation of compound 5. i) Methyl propiolate, CuI, K2CO3,
CH3CN, 408C, 24 h. ii) iPrMgCl, CuBr, LiBr, THF, À1008C, 1 h. iii) DIBAL, THF,
À788C–RT, overnight. DIBAL: diisobutylaluminium hydride.
et al., bromide 8 was treated with methyl propiolate, CuI, and
K2CO3 to afford 9 (75% yield)[15] No allene byproducts could be
observed in the crude reaction mixture. The iPr group was in-
stalled by an organocuprate addition under optimized condi-
tions (see below) yielding 10, followed by reduction with
DIBAL to give allylic alcohol 5. The reduction proceeded
smoothly, and only a quick purification by passage through
a small plug of silica was required to afford pure (E)-5 in 79%
yield.
Scheme 2. Preparation of compound 4. i) Literature: LDA, HMPA, iPrI, À788C,
4 h, 96%; this group: DMPU, DMSO, NMP, DMF, TMEDA, <20%. ii) LDA, iPrI,
À788C–RT, 4 h, 85%. iii) mCPBA, CH2Cl2, RT, 72 h. iv) K2CO3, EtOH, reflux, 4 h.
DMPU: N,N’-dimethylpropylene urea, TMEDA: N,N,N’,N’-tetramethylethylene-
diamine, HMPA: hexamethylphosphoramide, LDA: lithium diisopropylamide,
mCPBA: meta-chloroperoxybenzoic acid, NMP: N-Methyl-2-pyrrolidone.
of 6 by deconjugative alkylation of commercial ethyl crotonate
has earlier been reported by Herrmann et al. (Scheme 2i).[11]
They employed HMPA as an additive to form a strongly basic,
non-nucleophillic complex with LDA. In an effort to avoid the
use of significantly toxic or harmful substances such as HMPA,
several other additives were screened as potential replace-
ments. However, low conversions (determined by 1H NMR
spectroscopy) were obtained, and a significant amount of con-
jugated ester was formed as a byproduct. The best result was
obtained with DMPU, albeit with a low yield of 20%. Instead,
an alternative route (Scheme 2ii), employing alkylation of ethyl
3-butenoate with LDA and iPrI was developed and enabled
synthesis of 6 in high yield (85%), without the use of HMPA.
The stereoselectivity for introduction of the iPr group by
using an organocuprate was found to be very sensitive to the
reaction conditions (Table 1). At temperatures above À508C,
E:Z selectivity was poor (Table 1, entries 1 and 2). However, se-
lectivity dramatically increased when the reaction was carried
out below À508C (Table 1, entries 3 and 4). The use of THF as
solvent is crucial; Et2O had a negative effect on the selectivity,
even at low temperature (À788C; Table 1, entry 5). When the
reaction was carried out at À1008C, essentially only the E
product was produced (Table 1, entry 6). This protocol was also
amenable to scale-up (Table 1, entry 7). In asymmetric catalytic
hydrogenation it is often crucial that pure E or Z isomers be
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were also good, whereby the best results for alcohol 4 were
obtained with catalyst A (97% ee, 99% conversion), whereas
for the hydrogenation of 5, catalyst B gave the best results
(93% ee, 99% conversion). Both results were reproducible on
a 300 mg scale. In some reports, enantioselectivity can increase
if hydrogenation is carried out in solvents such as ClCH2CH2Cl
and CF3C6H5.[9i,16] A number of weakly coordinating solvents
were tested but did not lead to any improvements of the
enantioselectivities (for experimental details, see the Support-
ing Information).
Table 1. Optimization of the addition of the iPr group to 9.
Entry
T [8C]
Solvent
Scale [mg]
E:Z
1
2
3
4
5
6
7
À78 to À30
À40
THF
THF
THF
THF
Et2O
THF
THF
70
70
70
70
70
70
3000
4:1
6:1
À50
14:1
26:1
4:1
99:1
99:1
À78
À78
Our earlier work on the mechanism and origin of enantiose-
lectivity in iridium-catalyzed hydrogenation have resulted in
À100
À100
used. Thus, selective methods such as those developed herein
for the synthesis of compounds 4 and 10 are necessary, as
they avoid the tedious use of preparative chromatography or
crystallization to separate such isomers.
Two catalysts A and B (Table 2) having an imidazole and
a thiazole heterocyclic backbone, respectively, were evaluated
in the hydrogenation of substrates 4 and 5. Both of these sub-
strates have purely aliphatic substituents and are typically chal-
lenging substrates for obtaining high enantiomeric excess in
asymmetric catalytic hydrogenation. Screening was carried out
with CH2Cl2 as solvent, and the results for the asymmetric hy-
drogenation of compounds 4 and 5 are presented in Table 2.
For both catalysts A and B, high conversions were obtained
in the hydrogenations (Table 2, entries 1–4). Enantioselectivities
Scheme 4. Preparation of compounds 12 and 13. i) TsCl, Et3N, DMAP, CH2Cl2,
RT, overnight. ii)a) 1-Phenyl-1H-tetrazole-5-thiol, K2CO3, CH3CN, microwave,
908C, 20 min, filter; b) (NH4)6Mo7O24·4H2O (cat), H2O2, EtOH, reflux, overnight;
iii) PCC, CH2Cl2, RT, overnight.
a selectivity model that rationalizes the observed
enantioselectivities[10b,17] From the S configuration at
C-2 and C-7 in aliskiren, it follows that both hydro-
genated products 2 and 3 also should be S-configu-
rated. In accordance with the model, catalyst A
having 2-S configuration and catalyst B having 8-S
configuration were needed to produce 2 and 3, both
of which are S-configurated. This assignment was
indeed supported by experimental data (comparison
of optical rotation data reported for 1).[4b]
Table 2. Screening of asymmetric hydrogenation of compounds 4 and 5.[a]
The final part of the synthesis consists of joining
the two fragments into an E olefin by using the
Entry
Catalyst
Substrate
Conversion[b] [%]
ee[c] [%]
Julia–Kocienski reaction. Tosylation of 3 provided 11
in 91% yield (Scheme 4). The 1-phenyl-1H-tetrazole
sulfone 12 was prepared by a two-step thiolation
and molybdenum-catalyzed oxidation to produce 12
in 88% yield over two steps. Fragment 2, on the
other hand, was oxidized to the corresponding alde-
hyde 13 in good yield (91%).
1
2
A
B
99
77
97 À-S
72 À-S
3
4
A
B
99
99
83 +-S
93 +-S
For the Julia–Kocienski reaction, it is typically ob-
served that the use of phenyl-1H-tetrazole as the
heterocycle results in higher E selectivity compared
to benzothiazole and pyridine derivatives. To test
this hypothesis and to screen optimal conditions,
two isoamyl units (Scheme 5: 14 and 15) were
chosen as model substrates. A variety of bases and
solvents were screened, following a study by Morley
[a] Reaction conditions: 0.065 mmol substrate, 1.0 mol% catalyst, 0.5 mL CH2Cl2,
100 bar H2 for 4, 50 bar H2 for 5, 208C, 17 h. In the hydrogenation of 4, 1.5 mg of pol-
yvinylpyridine was added (see Supporting Information). [b] Determined by 1H NMR
spectroscopy. No side products were detected. [c] Determined by HPLC, SFC or GC on
a chiral stationary phase.
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Scheme 5. Study of the Julia reaction using isoamyl units 14 and 15.
Scheme 6. Preparation of 1 under optimized conditions and earlier reported
synthesis of aliskiren (patented route, see ref. [3]). X=leaving group.
et al.,[18] and the results are presented in Table 3. Increasing the
polarity of the solvent (toluene<Et2O<THF<DME) had a posi-
tive influence on selectivity toward the E product (Table 3, en-
tries 1–12). Potassium hexamethyldisilazide (KHMDS) was con-
sistently better than its Li and Na analogues, regardless of sol-
vent. With the exception of Et2O as solvent (Table 3, entries 4
Conclusion
Late-stage intermediate 1 in the synthesis of aliskiren was pre-
pared in 11 steps with an overall yield of 18% starting from 6.
The chirality at C-2 and C-7 of aliskiren was set up by asym-
metric hydrogenation of allylic alcohols 4 and 5. High enantio-
selectivities (97 and 93% ee) were achieved by using chiral N,P
ligated iridium catalysts. The product alcohols 2 and 3 were
then modified and combined by Julia–Kocienski reaction to se-
lectively produce the desired intermediate 1 in pure E configu-
ration.
Table 3. Screening results for isoamyl model substrates.
Entry
Solvent
toluene
M in MHMDS
E:Z
E [%]
1
2
3
Li
Na
K
1.5:1
1.7:1
7.0:1
60
63
88
4
5
6
Li
Na
K
2.9:1
2.1:1
6.3:1
74
68
86
Experimental Section
Et2O
THF
DME
All experimental details can be found in the Supporting Informa-
tion, which contains compound characterization and copies of
spectra of new compounds.
7
8
9
Li
Na
K
6.1:1
6.5:1
25.1:1
86
87
96
10
11
12
Li
Na
K
8.1:1
14.8:1
88.2:1
90
94
99
Acknowledgements
Energimyndigheten (The Swedish Energy Agency), Nordic
Energy Research (N-INNER II), The Swedish Research Council
(VR), The Knut and Alice Wallenberg Foundation, Swedish Gov-
ernmental Agency for Innovation Systems (VINNOVA) through
the Berzelii Center EXSELENT on Porous Materials, Stiftelsen
Olle Engkvist Byggmästare, and VR/SIDA for supporting this
work. Mr. Jianguo Liu thanks the Guangzhou Elite Scholarship
Council for a Ph.D. fellowship.
and 5), NaHMDS showed somewhat better E selectivity than
LiHMDS (Table 3, entries 1 vs. 2, 7 vs. 8, and 10 vs. 11). The
highest selectivity was obtained with a combination of DME
and KHMDS (99% E). These conditions were selected to pre-
pare 1 (Scheme 5). As anticipated, on combining fragments 12
and 13 under these conditions, only the E isomer was ob-
served by NMR spectroscopy, and 1 was isolated in 63% yield.
From the late-stage intermediate 1, aliskiren can be synthe-
sized by the Novartis protocol (Scheme 6): hydrolysis of ester
1 to the acid followed by halolactonization to furnish 17,
which has the desired stereochemistry for the synthesis of alis-
kiren after inversion at C-5 by SN2 substitution with azide.[3a–c]
The stereospecific halolactonization starting from the corre-
sponding dimethyl amide analogue of 1 has also been repor-
ted.[3g] Both protocols that enable the construction of the cor-
rect stereocenters at C-4 and C-5 rely on the use of pure E
olefin and are readily amendable to the highly E selective
Julia–Kocienski reaction used in this work.
Keywords: asymmetric synthesis · hydrogenation · iridium ·
olefination · total synthesis
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Published online on March 17, 2015
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