The development of a complementary pathway for the synthesis of aliskiren

Article abstract of DOI:10.1039/c4ob01963f

The synthesis of aliskiren (1), a recently marketed drug for the treatment of hypertension, is presented. The focus of our synthetic effort is to develop an efficient pathway for the synthesis of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-N,N,8-trimethylnon-4-enamide (2a), which has been used as the advanced intermediate toward aliskiren. After an extensive investigation of three different strategies designed to construct the E-olefin functionality in 2a by employing the olefin cross-metathesis, Horner-Wadsworth-Emmons (HWE), and Julia-type olefinations, we have established a new protocol for the synthesis of 2a with a substantially improved overall efficiency in terms of the yield (ca. 33%), and diastereo- and E/Z-selectivity. The key transformations were the Evans chiral auxiliary-aided asymmetric allylation for the synthesis of the appropriate chiral intermediates in excellent enantiomeric purity of higher than 97% ee and a modified Julia-Kocienski olefination for the highly selective construction of E-2a with up to 13.6:1 E/Z ratio from the chiral intermediates. Consequently, the results provide an appealing option for the synthesis of aliskiren. This journal is

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The development of a complementary pathway
for the synthesis of aliskiren†
Cite this: DOI: 10.1039/c4ob01963f
Le-Le Li,a,b Jin-Ying Ding,a Lian-Xun Gaoa and Fu-She Han*a,c
The synthesis of aliskiren (1), a recently marketed drug for the treatment of hypertension, is presented.
The focus of our synthetic effort is to develop an efficient pathway for the synthesis of (2S,7R,E)-2-iso-
propyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-N,N,8-trimethylnon-4-enamide (2a), which has been
used as the advanced intermediate toward aliskiren. After an extensive investigation of three different
strategies designed to construct the E-olefin functionality in 2a by employing the olefin cross-metathesis,
Horner–Wadsworth–Emmons (HWE), and Julia-type olefinations, we have established a new protocol for
the synthesis of 2a with a substantially improved overall efficiency in terms of the yield (ca. 33%), and dia-
stereo- and E/Z-selectivity. The key transformations were the Evans chiral auxiliary-aided asymmetric allyl-
ation for the synthesis of the appropriate chiral intermediates in excellent enantiomeric purity of higher
than 97% ee and a modified Julia–Kocienski olefination for the highly selective construction of E-2a with
up to 13.6 : 1 E/Z ratio from the chiral intermediates. Consequently, the results provide an appealing
option for the synthesis of aliskiren.
Received 16th September 2014,
Accepted 13th November 2014
DOI: 10.1039/c4ob01963f
www.rsc.org/obc
Introduction
Aliskiren 1 (Scheme 1) is a novel non-peptidic renin inhibitor1
and has been marketed as an orally active drug for the treat-
ment of hypertension.2 This molecule features the presence of
four chiral centers in an aliphatic carbon chain, which renders
the synthesis of this molecule extremely challenging. Neverthe-
less, the structural complexity as well as the fascinating bio-
logical activity of aliskiren has stimulated tremendous interest
of the community of synthetic and medicinal chemistry since
its discovery.3 Among a number of synthetic methods being
reported,3 the development of an effective approach for the
construction of the advanced intermediate 2a or 2b
(Scheme 1), whose structure contains two chiral centers and
an E-olefin, has been the focus of many investigations because
these intermediates can be flexibly converted into aliskiren
with high regio- and stereoinduction.3h
So far, three typical strategies have been developed for
accessing 2. These include the coupling of vinyl halide 3 with
a Grignard reagent generated from alkyl halide 43r–t (Path A),
aChangchun Institute of Applied Chemistry, Chinese Academy of Sciences,
5625 Renmin Street, Changchun, Jilin 130022, P. R. China. E-mail: fshan@ciac.ac.cn
bThe University of Chinese Academy of Sciences, Beijing 100864, P. R. China
cKey Lab of Synthetic Chemistry of Natural Substances, Shanghai Institute of
Scheme 1 Structures of aliskiren 1, the key intermediate 2 and the
general synthetic strategies.
Organic Chemistry, CAS, China
the base-promoted substitution reaction of aryl ketone 5 and
allylic bromide 63p,q (Path B), or the cross-metathesis of olefins
7 and 83d (Path C). Notably, the third protocol (Path C)
†Electronic supplementary information (ESI) available: Details of experimental
procedures, characterization data of NMR and HRMS, and copies of NMR
spectra and HPLC charts. See DOI: 10.1039/c4ob01963f
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established by Hanessian3d could allow for a rapid synthesis of
2b in five linear steps and in 38% overall yield from a known
intermediate. Despite these important advances, the develop-
ment of a more efficient synthesis remains highly desired
resulting from at least one of the following concerns of the
extant protocols such as the effective construction of C2 and
C7 chiral centers, or the E olefin.
After a careful analysis of the advantages and disadvantages
of the reported approaches, we thought that the key for an
efficient synthesis of 2 should rely on the establishment of
such a pathway that is capable of not only installing the chiral
centers with highly enantiomeric purity, but also constructing
the olefin moiety in high E-selectivity. Thus, three possible
routes were designed which we anticipated to construct the
E-2a at the late stage through the olefin cross-metathesis,
Horner–Wadsworth–Emmons (HWE), or Julia-type olefination
by employing the appropriately synthesized chiral precursors.
An extensive and detailed investigation into these synthetic
routes led eventually to the discovery that a pathway involving
the Evans asymmetric allylation and Julia–Kocienski olefina-
tion as the key transformations could be a highly appealing
option for the efficient synthesis of 2a. The notable advantages
offered by this new approach are that 2a could be furnished in
excellent E/Z selectivity of up to 13.6 : 1 from the appropriately
synthesized chiral precursors with excellent enantiomeric
purity of higher than 97% ee. In addition, high overall yield of
ca. 33% could be obtained for 2a in ten linear steps from the
commercially available materials. These advantages make the
current approach one of the appealing options for the efficient
synthesis of aliskiren. Finally, the synthesis of aliskiren from
the advanced intermediate 2a has also been successfully
demonstrated according to the known methods.3p,s Herein, we
present the detailed results of our investigation.
Scheme 2 Synthesis of olefins 12a–c and 16a–c. Reagents and con-
ditions: (a) LiHMDS (1.2 equiv.), allyl bromide (1.5 equiv.), THF, −78 °C to
rt, 96%; (b) LiHMDS (1.5 equiv.), 3,3-dimethylallyl bromide (1.5 equiv.),
THF, −78 °C to rt, 96%; (c) LiHMDS (1.2 equiv.), trans-1,4-dibromo-2-
butene (3.0 equiv.), THF, −78 °C to rt, 90%; (d) NaBH3CN (3.0 equiv.),
THF, 60 °C, 94%; (e) LiOH (2.0 equiv.), H2O2 (4.0 equiv.), THF–H2O, rt,
91% for 11a; 88% for 11b; 88% for 11c; (f) (COCl)2 (3.0 equiv.), DMF
(cat.), CH2Cl2, then Me2NH·HCl (2.0 equiv.), DMAP (5 mol%), Et3N
(4.0 equiv.), rt, 86% for 12a; 69% for 12b; 72% for 12c; (g) (COCl)2
(3.0 equiv.), DMF (cat.), CH2Cl2, then MeONH(Me)·HCl (2.0 equiv.), DMAP
(2 mol%), Et3N (4.0 equiv.), rt; (h) 14 (2.0 equiv.), n-BuLi (2.0 equiv.), THF,
−78 °C; (i) AlCl3 (2.0 equiv.), LiAlH4 (1.0 equiv.), Et2O, rt; three-step yield
for 16a: 70%; for 16b: 38%; for 16c: 26%.
cleavage of Evans’ chiral auxiliary in 10a–c afforded the corres-
ponding carboxylic acids 11a–c, which could be synthesized on
a scale of dozens of grams with constant efficiency and serve
as the versatile intermediates for the preparation of various
chiral precursors in our following studies. Accordingly, 11a–11c
were converted into the amides 12a–c and Weinreb amides
13a–c, respectively, through their acyl chlorides.8 The Weinreb
amides 13a–c were further reacted with the aryl lithium, gener-
ated in situ from aryl bromide 143d and n-BuLi, to give the aryl
ketones 15a–c. The enantiomeric purity of compound 15a was
higher than 97% ee as determined by chiral HPLC analysis
(see ESI†), reflecting that the Evans asymmetric allylation was
a powerful option for the synthesis of chiral precursors.
Finally, reduction of 15a–c by a combined use of LiAlH4 and
AlCl3 afforded the olefin 16a–c.3d,9
Results and discussion
Synthesis of 2a via the olefin cross-metathesis strategy
At the outset of our investigation, we planned to synthesize 2a
via the olefin cross-metathesis strategy. Although a general
rule for accurately predicting the selectivity of olefin cross-
metathesis such as homo- and heterogeneous selectivity, and
cis/trans stereoselectivity remains unavailable,4 intensive
studies have demonstrated that the outcome of the cross-meta-
thesis is markedly influenced by altering the steric and elec-
tronic properties of either reaction partners, or by choosing an
appropriate catalyst.5 Thus, a series of chiral olefin precursors
with different steric bulkiness were synthesized by utilizing
the Evans asymmetric allylation as the key transformation.6 As
outlined in Scheme 2, the reaction of commercially available 9
with allyl bromide (condition a) or 3,3-dimethylallyl bromide
(condition b) proceeded smoothly to give 10a and 10c, respect-
ively, in excellent yields. 10b was readily prepared via a two-
step procedure involving the allylation of 9 with trans-1,4-
dibromo-2-butene, affording 10b′, followed by reductive
removal of the bromo group with NaBH3CN.7 Hydrolytic
With the two types of olefins 12 and 16 in hand, we investi-
gated the cross-metathesis reaction. Screening of the catalysts
and solvents were carried out using 12a and 16a as the model
substrates. Some representative results are summarized in
Table 1. The Grubbs 1st generation catalyst (1st G) was less
effective with the best result obtained in 18% yield in CH2Cl2
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Table 1 Screening of catalysts and solventsa
Table 2 Cross-metathesis of various combinations of 12 and 16 in the
presence of a BQ additivea
Yieldb
(%)
Entry
Catalyst
Solvent
E/Zc
Yieldb
(%)
d
1
2
3
4
5
6
7
8
9
1st
G
G
G
CH2Cl2
CH2Cl2
n-Hexane
CH2Cl2
n-Hexane
PE
PhMe
(CH2)2Cl2
Cyclohexane
18
76
66
65
56
66
53
30
28
—
Entry
Substrate
Catalyst
Solvent
E/Zc
2nd
2nd
3.1
5.2
3.3
3.3
5.5
4.2
1
2
3
4
5
6
7
8
12a/16a
12a/16a
12a/16b
12a/16b
12b/16a
12b/16a
12b/16b
12b/16b
12b/16b
12b/16b
12b/16b
12b/16b
12b/16b
2nd H–G
PE
PE
PE
PE
PE
PE
PE
PE
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
88
72
72
78
82
80
72
80
68
62
62
67
66
3.9
4.2
4.6
4.2
3.0
4.2
4.1
4.3
5.7
6.6
7.0d
6.8e
6.7f
2
2
2
nd H–G
nd H–G
nd G
2
nd G
2nd H–G
2
2
2
nd G
2nd
G
nd H–G
nd G
d
2
nd G
2nd
—
d
G
—
2nd H–G
2
2
2
2
nd G
a Reaction conditions: 16a (0.5 mmol, 1.0 equiv.), 12a (1.5 mmol,
3.0 equiv.) and the catalyst (5 mol %) under reflux. b Isolated yield.
c E/Z ratio was determined by HPLC on a Hypersil ODS C18 column.
d Not determined.
9
nd H–G
nd G
10
11
12
13
nd G
2nd
2nd
G
G
a Unless otherwise noted, the reaction conditions were: 16 (0.2 mmol,
1.0 equiv.), 12 (0.8 mmol, 4.0 equiv.), catalyst (5 mol%), BQ (50 mol%)
in a solvent under reflux for 24 h. b Isolated yield. c The ratio of E/Z was
determined by HPLC on a Hypersil ODS C18 column. d 60 mol% of BQ
was used. e 70 mol% of BQ was used. f 80 mol% of BQ was used.
(entry 1). In contrast, the Grubbs 2nd generation catalyst
(2nd G) exhibited a much higher activity, giving the cross-meta-
thesis product 2a in high yield and moderate to moderately
high E/Z selectivity in CH2Cl2 and n-hexane solvents (entries 2
and 3). In addition, the Hoveyda–Grubbs 2nd generation cata-
lyst (2nd H–G) could also affect the reaction although the
overall efficiency was somewhat lower than the Grubbs 2nd stereoselectivity, we inspected the cross-metathesis of the steri-
generation catalyst (entries 4 and 5). Further examination of cally more hindered olefins. However, the results showed that
various solvents (entries 6–9) in the presence of the Grubbs the reaction was less sensitive to the steric nature of the sub-
2nd generation catalyst revealed that petroleum ether (PE) was strates in the PE solvent. Both the yield and E/Z selectivity
also a promising solvent (entry 6). Thus, through these pre- under various combinations of olefins such as 12a with
liminary studies, we found that CH2Cl2 or PE solvents coupled 1-methyl olefin 16b (entries 3 and 4), 1-methyl olefin 12b with
with the use of Grubbs 2nd or Hoveyda–Grubbs 2nd gene- 16a (entries 5 and 6), and 1-methyl olefin 12b with 1-methyl
ration catalysts were a promising combination for the cross- olefin 16b (entries 7 and 8) were almost identical to those
metathesis reaction. Here, it should be mentioned that the afforded by the combination of 1-unsubstituted olefin 12a and
structure of the major E-2a was determined by NMR and 16a. Interestingly, an increased E/Z ratio was observed when
HRMS analyses using a sufficiently pure sample isolated care- the PE solvent was replaced by CH2Cl2 (entries 9 and 10),
fully from the mixture of E and Z-2a by column chromato- although the yield was somewhat diminished. At this conjunc-
graphy on 200–300 mesh silica gel (E/Z >200 : 1 as determined ture, the effect of the molar equivalents of BQ on the reaction
by HPLC). The corresponding Z-2a was identified by the was re-optimized in order to improve the overall efficiency
1H-NMR combined with HPLC-MS analyses of a mixture of (entries 10–13). We found that the use of 60 mol% of BQ could
E- and Z-2a. The data were identical to the reported literature.3s
afford the best E/Z ratio of up to 7.0 : 1 without decrease in the
Having discovered the suitable solvents and catalysts, we yield (entry 11). Finally, it should be mentioned that ineffective
examined the effect of additives on the reaction since it has cross-metathesis was observed when either of the 1,1-dimethyl
been observed that, in many cases, the efficiency of olefin olefins 12c or 16c was used as the cross-metathesis partner.
cross-metathesis was dramatically influenced by varying the
During the course of our investigation, we noted that
additives.10 Accordingly, an array of Lewis and Brønsted acids, Hanessian and co-workers employed a very similar cross-meta-
bases, and oxidants were extensively examined. Unfortunately, thesis reaction as one of the key transformations in their syn-
most of the acidic and basic additives exhibited a detrimental thesis of aliskiren.3d Namely, in the presence of 20 mol% of
effect both to the yield and selectivity (data not shown). the Hoveyda–Grubbs 2nd generation catalyst, the cross-meta-
However, the addition of 1,4-benzoquinone (BQ) afforded an thesis of 16a and the olefin 17 bearing an ester functionality
improved yield in PE although the E/Z selectivity was some- delivered the cross product 2b in 60% yield and ca. 6.1 : 1 E/Z
what diminished (Table 2, entries 1 and 2). To improve the ratio under reflux for 3 days (Scheme 3). To compare with
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such as 1,4-diazabicyclo[2,2,2]octane (DABCO) was crucial for
improving the yield of 19 by suppressing the formation of
various side products.12
For the transformation of 18 or 19 to the corresponding
phosphonate esters 20 or 22, we investigated the copper-cata-
lyzed reductive coupling of dialkyl phosphite with N-tosyl-
hydrazone generated in situ from aldehyde and N-tosylhydrazine
as disclosed independently by Tang and Liang’s groups.13 This
new protocol takes the advantage of furnishing the phosphon-
ate esters directly from the aldehydes via a two-step one-pot
operation without the isolation of N-tosylhydrazone intermedi-
ates. Therefore, if the protocol works well for our substrates,
it would provide a straightforward option for the synthesis
of the desired phosphonate esters 20 or 22 to compare with
the conventional procedures, which, in principle, required a
multi-step transformation involving the reduction of the alde-
hyde to alcohol, conversion of alcohol to halide followed by
the Arbuzov reaction14 or by the nucleophilic displacement
of phosphinic halide with an organometallic reagent such
as organolithium and Grignard reagent formed from the
halide.15 Initial trials showed that the copper-catalyzed coup-
ling of dialkyl phosphite with the N-tosylhydrazone formed
from the amide aldehyde 18 and N-tosylhydrazine for produ-
cing 20 was ineffective under the reported conditions presum-
ably due to the influence of the amide functionality in 18.
However, 19 could be converted into the desired phosphonate
ester 22 in moderate yield (40–55%) via a one-pot reaction
through the intermediate 21. After a further optimization of
the reported reaction conditions, we could obtain 22 in 80%
yield by replacing the K2CO3 or Cs2CO3 base with K3PO4 and
the dioxane solvent with toluene, respectively.
Scheme 3 Cross-metathesis reaction reported by Hanessian et al.3d
Hanessian’s protocol, our cross-metathesis is somewhat more
effective for the construction of analogue 2a in terms of yield,
E/Z selectivity, the catalyst loading (5 mol%) and the reaction
time, presumably resulting from the different properties of
amide olefin 12a vs. the ester olefin 17 and the presence of a
BQ additive in the reaction system. However, both the yield
and E/Z selectivity of our procedure remained not sufficiently
high. In addition, the need of 5 mol% of the Grubbs 2nd gene-
ration catalyst is still a high loading. These drawbacks are
apparent obstacles when practical application for the synthesis
of aliskiren is under consideration. As such, we decided to
search an alternative pathway toward synthesizing 2a more
efficiently.
Synthesis of 2a via the HWE olefination strategy
Considering that Horner–Wadsworth–Emmons (HWE) olefina-
tion has various advantages such as high E-selectivity and the
ease of separation of the dialkyl phosphate by-product for the
preparation of alkenes,11 we investigated its application for the
synthesis of 2a. Accordingly, oxidation of the olefins 12a and
16a gave the aldehydes 18 (97% ee, see ESI†) and 19, respect-
ively, in high yield (Scheme 4). Here, it should be mentioned
that for the oxidation of 16a, the addition of an organic base
Next, the HWE olefination of 22 and 18 was examined
(Scheme 5). Disappointedly, extensive trials showed the reac-
tion did not proceed under an array of conditions – by varying
the bases, solvents, temperature and additives. 22 was recovered
completely in many cases. In stark contrast, control experi-
ments demonstrated that phosphonate 22 reacted uneventfully
with allyl bromide 23 to give the allylated phosphonate 24 in
Scheme 4 Synthesis of 20 and 22. Reagents and conditions: (a) OsO4
(1 mol%), NaIO4 (4 equiv.), THF–H2O (2 : 1), 0 °C, 69%; (b) OsO4 (1 mol%),
NaIO4 (4.0 equiv.), DABCO (4.0 equiv.), THF–H2O (2 : 1), 0 °C, 89%;
(c) TsNHNH2 (1.0 equiv.), toluene, rt, 45 min; then (EtO)2P(O)H
(5.0 equiv.), CuI (10 mol%), K3PO4 (6.0 equiv.), reflux, 80%.
Scheme 5 HWE reaction of 18 and 22, and control experiments.
Reagents and conditions: (a) allyl bromide (5.4 equiv.), n-BuLi
(1.5 equiv.), THF, −78 °C to rt, 69%; (b) 25 (1.5 equiv.), n-BuLi (1.5 equiv.),
THF, −78 °C to rt, 74%.
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69% yield. On the other hand, reaction of aldehyde 18 with
methyl 2-(diethoxyphosphoryl)acetate 25 could also proceed
efficiently to produce the α,β-unsaturated ester amide 26 in
74% yield. These results imply that the ineffective HWE reac-
tion between 18 and 22 may be resulted from the increased
steric bulkiness of both substrates. The detailed reasons
deserve a further clarification in our laboratory. Thus, we had
to give up this investigation and turn our attention to explore
other possible approaches.
Table 3 Optimization of the Julia–Kocienski olefination of sulfone 31
and aldehyde 18a
Yield
(%)b
E/Zc
Synthesis of 2a via the Julia–Kocienski olefination
Entry
31
Base
Solvent
Add. (equiv.)
The Julia-type olefination is also one of the most popularly
used protocols for accessing olefins.16 Typically, the Julia–
Kocienski olefination has been demonstrated to be a powerful
tool for the synthesis of E-form of nonconjugated 1,2-disubsti-
tuted alkenes.17 Owing to the exemplified advantages, we con-
ceived to synthesize 2a by employing the Julia–Kocienski
reaction. Accordingly, the aldehyde 19 was reduced to alcohol
27 with LiBH4 in quantitative yield (Scheme 6). Condensation
of 27 with 1-phenyl-1H-tetrazole-5-thiol 29a under Mitsunobu
conditions18 afforded the sulfide 30a in high yield. Alterna-
tively, the conversion of alcohol 27 into the corresponding
tosylate 28 followed by the substitution reaction with 29a–c
was also an efficient option for the synthesis of various sul-
fides 30a–c. Finally, oxidation of the sulfides19 proceeded
smoothly to give sulfones 31a–c.
Next, we examined the Julia–Kocienski olefination of sul-
fones 31 with aldehyde 18. The screening of the reaction con-
ditions was carried out using 31a and 18 as substrates. Some
representative data are shown in Table 3. A brief screening of
the solvents showed that THF was a better option in terms of
yield and E/Z selectivity (entries 1–3). In addition, among the
three bases being examined (entries 3–5), NaHMDS was the
optimal one which could afford 2a in high yield and moderate
1
2
3
4
5
6
7
8
31a
31a
31a
31a
31a
31a
31b
31c
31a
31a
31a
31a
31a
31a
LiHMDS
LiHMDS
LiHMDS
NaHMDS
KHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
Toluene
DMF
THF
THF
THF
DME
DME
DME
THF
DME
DME
DME
DME
DME
—
—
—
—
—
—
—
—
86
57
86
82
73
83
88
92
54
58
49
70
70
80
2.1
2.4d
3.3e
5.1
3.4
9.9 f
9.4
7.4
7.4
14.5
8.5
13.9
13.6
13.6
9
18-C-6 (2.0)
18-C-6 (2.0)
15-C-5 (2.0)
18-C-6 (1.0)
18-C-6 (0.5)
18-C-6 (0.25)
10
11
12
13
14
a Unless otherwise noted, the reaction conditions: 31 (0.2 mmol,
1.0 equiv.), 18 (0.8 mmol, 4.0 equiv.), base (0.4 mmol, 2.0 equiv.),
additive (x equiv.) in solvent from −78 °C (in THF) or −70 °C (in DME)
to r.t. b Isolated yield. c The ratio of E/Z was determined by HPLC on a
Hypersil ODS C18 column. d The reaction was performed from −40 °C
to r.t. since the reaction mixture was slightly frozen under lower
temperature. e Average value of two runs. f The reaction was performed
from −55 °C to r.t. since the reaction mixture was slightly frozen under
lower temperature. Abbr.: LiHMDS = lithium hexamethyldisilazide;
NaHMDS
hexamethyldisilazide; DMF
tetrahydrofuran; DME = 1,2-dimethoxyethane; 18-C-6 = 18-crown-6;
15-C-5 = 15-crown-5.
=
sodium hexamethyldisilazide; KHMDS
= potassium
=
N,N-dimethylformamide; THF
=
E/Z selectivity (entry 4). On the basis of these preliminary
results, the reaction parameters were re-examined using
NaHMDS as the base. Delightedly, we found that the E/Z
selectivity could be improved markedly from ca. 5.1 : 1 to 9.9 : 1
without affecting the yield when DME instead of THF was used
as the solvent (entry 4 vs. 6). An investigation into the effect of
different sulfones decorated by various R groups in the tetra-
t
zole moiety revealed that 31a (R = Ph) and 31b (R = Bu) could
afford the product in almost equally good efficiency as seen
from the yield and E/Z selectivity (entries 6 and 7). However,
31c (R = Me) gave a decreased E/Z ratio although the yield was
slightly increased (entry 8). Considering that 31a could be syn-
thesized more efficiently than 31b due to the higher yield for
the preparation of its precursor 30a (Scheme 6), sulfone 31a
Scheme 6 Synthesis of sulfones 31. Reagents and conditions: (a) LiBH4 was used as the substrate to screen the reaction conditions
(1.2 equiv.), THF, rt, quant.; (b) 29a (2.0 equiv.), PPh3 (1.5 equiv.), DEAD
(2.0 equiv.), THF, −40 °C, 80%; (c) TsCl (1.1 equiv.), Et3N (3 equiv.), DMAP
(0.05 equiv.), rt, 96%; (d) K2CO3 (5 equiv.), 29 (2.0 equiv.), 50 °C, 95% for
30a, 60% for 30b and 85% for 30c; (e) (NH4)6Mo7O24·4H2O (20 mol%),
toward further improving the reaction efficiency. At this con-
juncture, we inspected the effect of phase transfer catalysts
such as crown ethers since a recent report20 has exemplified
that the presence of such additives could influence consider-
ably the outcome of the Julia olefination. Indeed, we observed
30% H2O2 (20 equiv.), EtOH, rt, 94% for 31a, for 90% 31b and 98%
for 31c.
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Conclusions
In conclusion, we have developed an alternative route for the
synthesis of the advanced intermediate 2a toward aliskiren.
From the commercially readily available 9, 2a could be syn-
thesized in 33% overall yield via a ten-step procedure.
Although the steps of our synthesis are relatively longer and
the overall yield is slightly lower than the protocol developed
by Hanessian for the synthesis of analogue 2b (5 linear steps
from a known intermediate in 38% overall yield),3d the
pathway developed herein could afford the product with a
remarkably improved E/Z selectivity (E/Z = 13.6 : 1). Moreover,
the enantiomeric purity of the key chiral precursors 16a syn-
thesized through the Evans chiral auxiliary-aided asymmetric
allylation in this work is higher than that synthesized through
the Stoltz Pd-catalyzed asymmetric protocol3d,21 (97% vs. 90%
ee). Owing to these advantages, we believe that the method
presented in this work should be a complementary route for
the synthesis of aliskiren. The synthesis of aliskiren from 2a
has also been demonstrated according to the known proce-
Scheme 7 Synthesis of aliskiren (1).
that the addition of 2.0 equiv. of 18-crown-6 could lead to a dures.3p,s Further optimization of the process toward large
substantial increase in E/Z selectivity either in THF or in DME scale synthesis is currently underway.
(entries 4 vs. 9, and 6 vs. 10). Notably, the E/Z ratio was
improved to 14.5 : 1 in DME, although the yield of 2a signifi-
cantly diminished in this solvent (entry 10). As a comparison,
Experimental section
the addition of 15-crown-5 exhibited a detrimental effect both
General methods
to the yield and stereoselectivity (entry 11). Finally, a brief
Unless otherwise noted, all solvents were purified according to
the standard procedures. Allyl bromide, (COCl)2, and (EtO)2POH
were distilled prior to use. Other reagents were of reagent grade
and used without purification. The 1H-NMR spectra were
recorded at 600, 400, or 300 MHz (Bruker AV) in CDCl3 or
DMSO-d6. The 13C-NMR spectra were recorded at 150 or
100 MHz in CDCl3 or DMSO-d6. The 31P-NMR spectra were
recorded at 162 MHz in CDCl3. Chemical shifts are given in
ppm relative to TMS or the appropriate solvent peak. Coupling
constants (J values) are reported in hertz (Hz). High resolution
mass spectra (HRMS) are measured using an IonSpec Ultima 7.0
TFT-ICR-MS instrument (IonSpec, USA) with a Waters Z-spray
source. HPLC analysis was performed on Shimadzu (LC 20AD,
UV detection monitored at 254 nm) or Shimadzu (LC 6AD, UV
detection monitored at 254 nm). C18 column for E/Z selectivity
measurements (Hypersil ODS 5 μm, 4.6 mm × 250 mm) was pur-
chased from Dalian Elite Analytical Instruments Co., Ltd.
A Chiralpak AD-H column for enantiomeric excess measurements
was purchased from Daicel Chemical Industries, Ltd. The optical
rotation value was measured by a Perkin Elmer 341LC polari-
meter operating on the sodium D-line (589 nm), using a
100 mm path-length cell and are reported as: [α]TD (concen-
tration in g per 100 mL, solvent). Column chromatography was
performed on silica gel 100–200 mesh or 200–300 mesh.
optimization of the molar equivalents of 18-crown-6 (entries
12–14) revealed that the presence of 0.25 equiv. of 18-crown-6
could deliver 2a not only in high yield (80%) but also in excel-
lent E/Z selectivity (13.6 : 1) (entry 14).
Having established an efficient route for the synthesis of
the advanced intermediate 2a, we implemented the final syn-
thesis of aliskiren (1) by referring to the reported procedur-
es.3p,s Namely, bromolactonization of 2a with NBS followed
by a simple recrystallization of the crude product afforded
pure lactone 32 (Scheme 7). The NMR spectroscopic and the
specific rotation value of the intermediate 32 were consistent
with the reported data {synth., [α]2D0 +39.2 (c 1.0, CHCl3);
Lit.,3s [α]D25 +44.2 (c 1.0, CHCl3)}. The data further confirmed
that E-2a is obtained as the major product from the Julia–
Kocienski olefination. Substitution of Br with NaN3 and amid-
ation of the lactone moiety in 32 proceeded uneventfully to
give the azide 33. Finally, hydrogenolysis of the N3 group in
33 gave aliskiren 1. Here, we should mention that, although
not investigated carefully, it seems that the free aliskiren
is not sufficiently stable during hydrogenolysis and the
subsequent handling. A small amount of the less polar by-
product was often formed as indicated by the TLC monitor-
ing. This may result from the partial oxidation of the product
under ambient conditions. After some trials, it was found
that the addition of ethanolamine in the reaction system and
trapping the product with HCl solution in MeOH could afford
General synthesis of 2a via the olefin cross-metathesis
pure aliskiren as its HCl salt. The NMR data of both the HCl A round-bottom flask equipped with a condenser and a mag-
and hemifumarate salt of aliskiren is identical to the reported netic stirrer bar was charged with 16 (1.0 equiv.), 12 (3.0 or
data.3j,u
4.0 equiv.), additives (added or not) and 5 mol% of catalyst under
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a nitrogen atmosphere. The reaction vessel was flushed with
nitrogen. Then a solvent was added via a glass syringe. The
resulting reaction mixture was refluxed for 24 h under a nitro-
gen atmosphere. The solvent was then removed under reduced
pressure. The product was isolated by column chromatography
on silica gel with ethyl acetate and hexane (v/v = 1 : 5) as an
eluent to give 2a as a slightly yellow oil.
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General synthesis of 2a via the Julia–Kocienski olefination
A dried tube equipped with a magnetic stirrer was charged
with 31 (0.2 mmol, 1.0 equiv.) and flushed with nitrogen. Then
a dried solvent (2.5 mL) was added via a glass syringe. Unless
otherwise noted, the solution was cooled to −70 °C and then a
solution of the MHMDS base (0.4 mmol in solvent (1 mL),
where M = Li, Na, or K) was added dropwise. After being
stirred at −70 °C for 1 h, aldehyde 18 (0.8 mmol in solvent
(1 mL)) was added dropwise. The resulting reaction mixture
was stirred at −70 °C for 1 h and then allowed to warm gradu-
ally to room temperature and stirred for a few hours until 31
had disappeared, as monitored by TLC. The reaction mixture
was quenched with brine and diluted with CH2Cl2. The
organic layer was separated, dried over Na2SO4, filtered, con-
centrated and purified by flash column chromatography on
silica gel with a mixed ethyl acetate and hexane (v/v = 1 : 2) as
an eluent to give 2a as a slightly yellow oil.
Acknowledgements
Financial support from the NSFC (21272225), and the Key Lab-
oratory of Synthetic Chemistry of Natural Substances, SIOC, is
acknowledged.
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