A total synthesis of aliskiren

Article abstract of DOI:10.1002/hlca.201200425

A total synthesis of aliskiren (20) was accomplished. A key in our synthesis was to use the symmetric trans-cisoid-trans-bis-lactone 1 as a precursor. It was expediently prepared by three different routes (Scheme 2). Appending the end groups and functional group transformations completed the synthesis (Scheme 3). Copyright

Full text of DOI:10.1002/hlca.201200425

Helvetica Chimica Acta – Vol. 95 (2012)
1937
A Total Synthesis of Aliskiren
by Gyeok Nam and Soo Y. Ko*
Department of Chemistry, Ewha Womans University, Seoul 120-750, Korea
(phone: þ822-3277-3283; fax: þ822-3277-2384; e-mail: sooyko@ewha.ac.kr)
Dedicated to Professor Dieter Seebach on the occasion of his 75th birthday
A total synthesis of aliskiren (20) was accomplished. A key in our synthesis was to use the symmetric
trans-cisoid-trans-bis-lactone 1 as a precursor. It was expediently prepared by three different routes
(Scheme 2). Appending the end groups and functional group transformations completed the synthesis
(Scheme 3).
Introduction. – The hydroxyethylene dipeptide isostere has been designed to mimic
the transition state of the peptide bond cleavage, and has been incorporated in the
structures of several drug molecules that act as protease inhibitors [1]. Among them is
aliskiren, a renin inhibitor, which is unique for being the first orally active, efficient,
non-peptidic drug for treatment of hypertension [2]. Aliskiren is currently marketed
under the trade names Tekturna and Resilez.
The structure of aliskiren is fairly complex as drug molecules go. A key in the
synthesis of aliskiren is the construction of the octanoic acid backbone, with the control
of the configurations at the stereogenic centers at C(2), C(4), C(5), and C(7)
(Scheme 1). Diverse synthetic approaches have been reported in the literature. A
majority of them, including the original Novartis synthesis [3], utilized convergent
synthetic strategies, wherein two chiral fragments had been separately prepared by the
aid of various chiral auxiliary groups, and later assembled at or around the amino
alcohol function [3 – 6]1). Hanessian and co-workers reported two very distinct
synthetic approaches to aliskiren [7]. In the first one, an amino acid chiral pool starting
material was converted to a C5 fragment, the isopropyl group (at C(7)) having been
incorporated with a highly selective asymmetric induction. A C3 fragment was then
linked, again the required configuration having been controlled by asymmetric
induction. In the second approach, a single enantiomerically pure compound, with the
isopropyl group already in place with the correct (S)-configuration, was converted to
two different fragments, which were later joined.
We noted a ꢀpseudo-symmetricꢁ nature of the octanoic acid backbone. The two
isopropyl groups are attached at the palindromic C(2) and C(7) atoms, both with (S)-
configurations, and the two heteroatoms (amino alcohol function) are at C(5)/C(4),
both with (S)-configurations. The use of a symmetric precursor, which would be
1
)
A nice summary of the literature synthetic strategies can be found in [6a].
ꢂ 2012 Verlag Helvetica Chimica Acta AG, Zꢃrich

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Helvetica Chimica Acta – Vol. 95 (2012)
expediently constructed, then later desymmetrized by sequentially introducing the end
groups, would offer an efficient pathway to aliskiren.
Results and Discussion. – We envisaged the trans-cisoid-trans-bis-lactone 1 to be a
well-suited symmetric precursor for our synthesis of aliskiren (20; Scheme 1). The two
isopropyl groups are in place with the correct (S)-configuration, and the lactone
functions are amenable for introducing the end groups. The two O-functions in the
center are where the amino alcohol function is located in the target molecule 20 C(4)/
C(5). Synthesis of aliskiren would require one of the two O-functions to be
regioselectively transformed to an amino group with a retention of the configuration.
Scheme 1. Synthetic Strategy to Aliskiren (20)
The trans-cisoid-trans-bis-lactone 1 was prepared via three different synthetic
routes (Scheme 2). In Path I, two isopropyl groups were introduced concurrently and
stereoselectively at both C(a) atoms of the known, unsubstituted bis-lactone 2 [8] in
three steps: aldol addition of the bis-enolate to acetone, dehydration, and reduction.
The aldol addition in the presence of lithium bis(trimethylsilyl)amide (LiHMDS) took
place stereoselectively trans to the existing substituent (! 3), dehydration prompted
by PCl5 produced the diisopropenyl-substituted compound 4 [9], and catalytic
hydrogenation yielded the desired trans-cisoid-trans-bis-lactone 1. Direct isopropyla-
tion of the bis-enolate was not successful. In Path II, protected dimethyl l-tartrate 5
was the starting material. Following a reduction with diisobutylaluminium hydride
(DIBAL) to the dialdehyde stage, an in situ HornerꢀEmmonsꢀWadsworth reaction
with the isopropyl-substituted ester (EtO)2P(¼O)ꢀCH(CHMe2)ꢀCOOEt (6) [10]
brought us, in a single step from the commercially available starting material to the
stage with the complete carbon skeleton of 1, i.e., to 7. Product 7 was in fact a mixture of
cis- and trans-isomers, in which the cis,cis-isomer was major (4 to 5 :1). Upon
unmasking the diol function, only the cis,cis-isomer underwent double cyclization to
produce bis-lactone 8. Reduction of 8 took place from the opposite side with respect to
the existing substituent to produce the cis-cisoid-cis-bis-lactone 9. Equilibration under
basic conditions (1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)/DMF) resulted in epime-
rization, albeit with a disappointing selectivity (ca. 1:1), to produce the desired trans-
cisoid-trans-bis-lactone 1. When the order of the last two steps, i.e., deprotection and
reduction, was reversed, the bis-lactone product was obtained as a mixture of three
diastereoisomers, i.e., 1, 9, and the trans-cisoid-cis-isomer. Once again, epimerization

Helvetica Chimica Acta – Vol. 95 (2012)
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Scheme 2. Synthetic Pathways to trans-cisoid-trans-Bis-lactone 1
shifted the distribution toward the desired trans-cisoid-trans-bis-lactone 1, interestingly,
however, with a selectivity worse than in the above-described case under supposedly
equilibrating conditions.
In contrast to Paths I and II described above wherein the configurations of the
target stereogenic centers C(4)/C(5) originated from the enantiomerically pure starting
materials and those of C(2)/C(7) (isopropyl-substituted stereogenic centers) were
induced relative to those at C(4)/C(5), Path III of the synthesis of the trans-cisoid-
trans-bis-lactone 1 had the isopropyl-substituted target stereogenic centers C(2)/C(7)

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Helvetica Chimica Acta – Vol. 95 (2012)
installed first, by means of Evansꢁ chiral auxiliary, i.e., a substituted oxazolidinone.
Thus, allylation of the enolate derived from 11 (obtained from 10) proceeded with a
high stereoselectivity (!12) [3a]. Grubbsꢁ alkene metathesis reaction yielded then the
symmetric trans-alkene derivative 13 as the major product [11]. The initial attempt at
the Sharpless asymmetric dihydroxylation (AD reaction) of 13 with AD-mix-a was too
slow to be practical under the standard conditions. With a higher catalyst loading (twice
the standard protocol) at room temperature, the dihydroxylation took place, followed
by in situ lactonization, to produce bis-lactone products. The stereoselectivity was only
modest (3.3 :1), however, and the desired stereoisomer 1 was isolated in 43% yield
after a chromatographic purification. The low reactivity and poor stereoselectivity were
probably due to the steric hindrance exerted by the isopropyl groups at the homoallylic
C-atoms. When the Evans auxiliaries (i.e., the oxazolidinone moieties) were replaced
by methyl ester functions, the AD reaction was still slow, and the stereoselectivity was
not much improved2). A practically more convenient procedure was to use OsO4/4-
methylmorpholine 4-oxide (NMO). With the achiral reagents, the bis-lactone product
was formed as a 1:1 mixture of trans-cisoid-trans and cis-cisoid-cis-diastereoisomers,
i.e., of 1 and the enantiomer of 9, which were separated by column chromatography
(SiO2) to yield the desired isomer 1 in 45% yield.
Having obtained the symmetric intermediate 1, remaining tasks were appending the
right- and left-end groups of 20 (Scheme 3), and functional-group transformations
while taking into consideration the required configuration. The aryl end group was
introduced by reacting bis-lactone 1 with the corresponding aryllithium (prepared from
the aryl bromide). Only one of the lactone rings was opened even with a slight excess of
the aryllithium, and due to the symmetric nature of bis-lactone 1, it did not matter
which one. The benzoyl group in the resulting product 14 was reduced to the benzyl
group with H2 on Pd/C (!15). The ring-opening 1 ! 14 also released one of the OH
functions, the one that needed to be converted to the amino function of aliskiren (20)
with retention of the configuration. This meant that we needed to perform double
substitution reactions for this O ! N conversion. Thus, OH group of 15 was mesylated
(!16). Subsequent SN2 reactions first by Brꢀ (!17), then by N3ꢀ (!18) placed the N-
function at the right place with the correct configuration (S). The remaining lactone
ring was then opened with the right-end amino group, i.e., with 3-amino-2,2-
dimethylpropanamide, in the presence of propanoic acid [12]. Reduction of the azide
group of the obtained amide 19 yielded aliskiren (20).
In conclusion, a total synthesis of aliskiren was accomplished. A key in our synthesis
was to use the symmetric trans-cisoid-trans-bis-lactone 1 as a precursor. It was
expediently prepared by three different routes. Appending the end groups and
functional-group transformations completed the synthesis.
Experimental Part
General. Flash column ohromatography (FC): silica gel. TLC: silica gel glass-backed plates. IR
Spectra: thin films on KRS-5 plates; in cmꢀ1. 1H- and 13C-NMR Spectra: at 250 or 300 (1H) and 62.5 or
75 MHz (13C); d in ppm rel. to Me4Si as an internal standard, J in Hz.
2
)
This did not seem to be a case of the mis-matched double stereoselection. The AD reactions with
AD-mix-b were equally slow and the stereoselectivity modest (1:3).

Helvetica Chimica Acta – Vol. 95 (2012)
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Scheme 3. Synthetic Pathway from Bis-lactone 1 to Aliskiren (20)
(2S,2’S,4S,4’S)-Tetrahydro-4,4’-bis(1-hydroxy-1-methylethyl)-[2,2’-bifuran]-5,5’(2H,2’H)-dione (3).
A soln. of bis-lactone 2 (0.190 g, 1.12 mmol) in THF (5 ml) was cooled to ꢀ 788. Then, 1m LiHMDS in
THF (2.6 ml, 2.6 mmol) was added dropwise, and the mixture was stirred at ꢀ788 for 1 h. Anh. acetone
(0.21 ml, 2.58 mmol) was added, and the mixture was stirred for 1 h at ꢀ 788. The reaction was quenched
by adding sat. aq. NH4Cl soln. and Et2O. The mixture was warmed to r.t. and then extracted with CHCl3.
The combined org. phase was dried (Na2SO4) and concentrated and the residue purified by FC (AcOEt/
1
EtOH 20 :1): 3 (0.096 g, 30%). FT-IR: 3380, 3020, 1749, 1364, 1217. H-NMR (CDCl3): 4.54 – 4.59 (m,
2 H), 2.91 (t, J ¼ 9.6, 2 H); 2.82 (s, 2 H); 2.28 – 2.47 (m, 4 H); 1.37 (s, 6 H); 1.27 (s, 6 H). 13C-NMR
(CDCl3): 177.3; 78.4; 71.2; 49.0; 27.7; 27.1; 26.4.
(2S,2’S,4S,4’S)-Tetrahydro-4,4-bis(1-methylethenyl)-[2,2’-bifuran]-5,5’(2H,2’H)-dione (4). A soln. of
3 (0.061 g, 0.214 mmol) in CH2Cl2 (6 ml) was cooled to 08. PCl5 (0.115 g, 0.515 mmol) in CH2Cl2 (1 ml)
was added, and the mixture was stirred for 3.5 h. The reaction was quenched by adding sat. aq. NaHCO3
soln. Extractive workup with CH2Cl2, drying (Na2SO4), and FC (hexane/AcOEt 2 :1) yielded 4 (0.025 g,
47%). FT-IR: 3021, 2360, 1777, 1153. 1H-NMR (CDCl3): 5.01 (dd, J ¼ 15.9, 2.7, 4 H); 4.56 – 4.62 (m, 2 H);
3.47 – 3.53 (m, 2 H); 2.48 – 2.58 (m, 2 H); 2.32 – 2.42 (m, 2 H); 1.82 (s, 6 H). 13C-NMR (CDCl3): 175.9;
139.6; 114.9; 78.2; 46.7; 29.6; 20.3.

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Helvetica Chimica Acta – Vol. 95 (2012)
(2S,2’S,4S,4’S)-Tetrahydro-4,4’-bis(1-methylethyl)-[2,2’-bifuran]-5,5’(2H,2’H)-dione (1). To a soln. of
4 (0.022 g, 0.088 mmol) in AcOEt. Pd/C (10 mg) was added, and the mixture was stirred under H2 (g) for
15 h at r.t. The mixture was filtered through a pad of Celite, which was further washed with AcOEt. The
combined filtrate and washings were concentrated. FC (hexane/AcOEt 3 :1) yielded 1 (0.020 g, 88%).
1
FT-IR: 2360, 1978, 1869, 1777. H-NMR (CDCl3): 4.47 – 4.53 (m, 2 H); 2.74 – 2.83 (m, 2 H); 2.28 – 2.38
(m, 2 H); 2.14 – 2.24 (m, 4 H); 1.04 (d, J ¼ 6.9, 6 H); 0.95 (d, J ¼ 6.8, 6 H). 13C-NMR (CDCl3): 177.9; 78.5;
44.7; 28.7; 25.9; 20.3; 18.2.
(2E,2’E)-Diethyl 2,2’-{[(4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl]dimethylidene}bis[3-methylbu-
tanoate] (7). A soln. of 5 (6.54 g, 30 mmol) in toluene (110 ml) was cooled to ꢀ 788. Then 1m DIBAL
in hexane (72 ml, 72 mmol) was added slowly, and the mixture was stirred at ꢀ 788 for 5 h 10 min.
In the meantime, 60% NaH in oil (4.320 g) and THF (50 ml) were cooled to 08 in a seperate flask.
Ethyl 2-(diethoxyphosphinyl)-3-methylbutanoate (6) was added, and the mixture was stirred at 08 for 2 h
40 min. This mixture was then added slowly to the first reaction flask via a syringe. The mixture was
stirred for 21 h 40 min, while the temp. slowly rose to r.t. The reaction was quenched by adding H2O.
Extractive workup (AcOEt, 10% citric acid), drying (Na2SO4), and FC (hexane/AcOEt 8 :1) yielded 7
1
(9.465 g, 82%) cis-cis/trans-cis-product 4 to 5 :1. H-NMR (CDCl3): cis-cis-isomer: 5.64 – 5.72 (m, 2 H);
4.74 – 4.82 (m, 2 H); 4.22 (q, J ¼ 7.2, 4 H); 2.67 – 2.77 (m, 2 H); 1.46 (s, 6 H); 1.32 (t, J ¼ 7.2, 6 H); 1.08 (t,
J ¼ 7.5, 12 H); trans-cis-isomer: 6.45 (d, J ¼ 8.9, 1 H); 5.63 – 5.71 (m, 1 H); 4.74 – 4.86 (m, 1 H); 4.55 (t,
J ¼ 8.4, 1 H); 4.17 – 4.26 (m, 4 H); 2.74 – 2.79 (m, 2 H); 1.49 (s, 3 H); 1.47 (s, 3 H); 1.29 – 1.34 (m, 6 H);
1.05 – 1.21 (m, 12 H).
(2S,2’S)-4,4’-Bis(1-mehylethyl)[2,2’-bifuran]-5,5’(2H,2’H)-dione (8). To 7 (0.850 g, 2.22 mmol;
mixture of stereoisomers) in a cooling bath maintained at ꢀ 108, CF3COOH/EtOH 7:3 (v/v; 30 ml),
which had been cooled to ꢀ 108, was added slowly. The mixture was stirred for 2 h, while the temp. was
allowed to slowly rise to 08, and after a further 1.5 h stirring, the temp. had reached r.t. Evaporation and
1
FC (hexane/AcOEt 3 :1) yielded 8 (0.614 g, 81%). H-NMR (CDCl3): 6.93 (s, 2 H); 5.18 (s, 2 H); 2.69
(quint., J ¼ 6.9, 2 H); 1.18 (d, J ¼ 6.9, 12 H).
(2S,2’S,4R,4’R)-Tetrahydro-4,4’-bis(1-methylethyl)[2,2’-bifuran]-5,5’(2H,2’H)-dione (9). To
8
(1.150 g, 4.6 mmol) in EtOH (20 ml), Pd/C (0.46 g) was added, and the mixture was stirred under H2
(g) for 16 h at r.t. The mixture was filtered through a pad of Celite, which was washed with AcOEt and
EtOH. The combined filtrate and washings were concentrated. FC (hexane/AcOEt 3 :2) yielded 9
(1.170 g, 100%). 1H-NMR (CDCl3): 4.38 – 4.46 (m, 2 H); 2.59 – 2.69 (m, 2 H); 2.18 – 2.31 (m, 4 H); 2.00 –
2.12 (m, 2 H); 1.08 (d, J ¼ 6.6, 6 H); 0.96 (d, J ¼ 6.9, 6 H).
Compound 1 from 9. To a soln. of 9 (0.136 g, 0.536 mmol) in DMF (10 ml), DBU (0.53 ml,
3.52 mmol) was added, and the mixture was heated to reflux for 12 h. After cooling to r.t., sat. aq. NH4Cl
soln. was added, and the mixture was extracted with CHCl3. The combined org. phase was dried
(Na2SO4) and concentrated and the residue subjected to FC (hexane/AcOEt 2 :1): 1 (0.043 g, 31%).
(4S)-3-(3-Methyl-1-oxobutyl)-4-(phenylmethyl)oxazolidin-2-one (11). To (4S)-4-benzyloxazolidin-
2-one (10; 7.09 g) in THF (60 ml), Ph3CH (30 mg) was added. The soln. was cooled to ꢀ 788. 2m BuLi in
hexane (20 ml, 40 mmol) was added slowly, and the mixture was stirred for 1 h. Then, 3-methylbutanoyl
chloride (7.36 ml, 60 mmol) was added slowly, and the mixture was stirred at ꢀ 788 for 30 min before it
was warmed to r.t. where it was stirred for further 2 h. The reaction was quenched by adding 10% aq.
K2CO3 soln. Extractive workup (AcOEt-brine), drying (Na2SO4), and FC (hexane/AcOEt 4 :1) yielded
11 (10.41 g, 100%). FT-IR: 3544, 3381, 3028, 2960, 2873, 2360, 1962, 1782, 1699, 1454, 1389, 1211, 1096.
1H-NMR (CDCl3): 7.20 – 7.37 (m, 5 H); 4.64 – 4.71 (m, 1 H); 4.13 – 4.23 (m, 2 H); 3.32 (dd, J ¼ 13.4, 3.0,
1 H); 2.71 – 2.94 (m, 3 H); 2.17 – 2.27 (m, 1 H); 0.99 – 1.04 (m, 6 H). 13C-NMR (CDCl3): 172.7; 153.5;
135.4; 129.4; 129.0; 127.3; 66.1; 55.2; 44.0; 38.0; 25.0; 22.6; 22.5.
(4S)-3-[(2S)-2-(1-Methylethyl)-1-oxopent-4-en-1-yl]-4-(phenylmethyl)oxazolidin-2-one (12). To a
soln. of 11 (4.31 g, 16.4 mmol) in THF (40 ml) at ꢀ 788, 1m NaHMDS in THF (24.7 ml, 24.7 mmol) was
added slowly, and the mixture was stirred for 70 min. Allyl bromide (freshly distilled; 4.83 ml, 65.6 mmol)
was added and the mixture was stirred for 8.5 h, during which the temp. rose from ꢀ 788 to ꢀ 458. The
reaction was quenched by adding sat. aq. NH4Cl soln. Extractive workup (AcOEt, brine), drying
(Na2SO4), and FC (hexane/AcOEt 4 :1) yielded 12 (4.084 g, 83%). FT-IR: 3081, 2965, 2253, 1778, 1692,
1
1385. H-NMR (CDCl3): 7.24 – 7.35 (m, 5 H); 5.78 – 5.92 (m, 1 H); 5.01 – 5.15 (m, 2 H); 4.69 – 4.74 (m,

Helvetica Chimica Acta – Vol. 95 (2012)
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1 H); 4.14 – 4.17 (m, 2 H); 3.84 – 3.92 (m, 1 H); 3.33 (dd, J ¼ 13.4, 3.3, 1 H); 2.66 (dd, J ¼ 13.3, 10.1, 1 H);
2.41 – 2.51 (m, 2 H); 1.98 – 2.19 (m, 1 H); 1.00 (d, J ¼ 6.6, 6 H). 13C-NMR (CDCl3): 175.8; 153.3; 135.6;
135.5; 129.5; 128.9; 127.3; 116.9; 65.8; 55.7; 48.2; 38.1; 33.7; 30.3; 20.9; 19.2.
(2S,4E,7S)-2,7-Bis(1-methylethyl)-1,8-bis[(4S)-2-oxo-4-(phenylmethyl)oxazolidin-3-yl]oct-4-ene-
1,8-dione (13). To a soln. of 12 (1.528 g, 5.07 mmol) in CH2Cl2 (20 ml), Grubbs catalyst (2nd generation;
86 mg) was added, and the mixture was heated to reflux for 27 h. Solvent evaporation and FC (hexane/
AcOEt 4 :1) yielded 13 (1.168 g, 80%). FT-IR: 3022, 2965, 1961, 1779, 1694, 1386, 1349. 1H-NMR
(CDCl3): 7.22 – 7.36 (m, 10 H); 5.50 – 5.54 (m, 2 H); 4.63 – 4.68 (m, 2 H); 4.08 – 4.16 (m, 4 H); 3.74 – 3.81
(m, 2 H); 3.33 (dd, J ¼ 13.1, 3.0, 2 H), 2.68 (dd, J ¼ 10.2, 10.1, 2 H); 2.28 – 2.48 (m, 4 H); 1.97 – 1.99 (m,
2 H); 0.93 (t, J ¼ 6.3, 12 H). 13C-NMR (CDCl3): 175.7; 153.3; 135.7; 129.5; 129.4; 129.0; 127.2; 65.8; 55.6;
48.7; 37.9; 32.0; 30.1; 20.8; 19.2.
Compound 1 from 13. A soln. of 13 (3.478 g, 6.05 mmol), OsO4 (4% aq. soln.; 0.381 g, 0.060 mmol),
and 4-methylmorpholine 4-oxide (1.42 g, 12.1 mmol) in acetone/H2O 8 :1 (v/v; 36 ml) was stirred at r.t.
for 21 h. The reaction was quenched by adding NaHSO3 soln. Extractive workup (AcOEt, brine), drying
(Na2SO4), and FC (hexane/AcOEt 2 :1) yielded 1 (0.692 g, 45%).
(3S,5S)-Dihydro-5-{(1S,3S)-1-hydroxy-3-[4-methoxy-3-(3-methoxypropoxy)benzoyl]-4-methylpen-
tyl}-3-(1-methylethyl)furan-2(3H)-one (14). To a soln. of 4-bromo-1-methoxy-2-propoxybenzene
(0.335 g, 1.22 mmol) in THF (7 ml) at ꢀ 788, 1.7m t-BuLi in pentane 1.43 ml, 2.44 mmol) was added
slowly, and the mixture was stirred at ꢀ 788 for 1 h 50 min. A soln. of 1 (0.238 g, 0.936 mmol) in THF
(6 ml) was also cooled to ꢀ 788 and added rapidly to the above soln. The entire mixture was stirred at
ꢀ 788 for 19 h. The reaction was quenched by adding sat. aq. NH4Cl soln. The mixture was extracted with
AcOEt. The combined org. phase was dried (Na2SO4) and concentrated, and the residue subjected to FC
(hexane/AcOEt 2 :1): 14 (0.231 g, 55%). FT-IR: 3442, 3018, 2964, 2931, 1760, 1661, 1592, 1514, 1428,
1263, 1130, 1022. 1H-NMR (CDCl3): 7.65 (dd, J ¼ 8.4, 2.1, 1 H); 7.58 (d, J ¼ 2.1, 1 H); 6.90 (d, J ¼ 8.4, 1 H);
4.22 – 4.30 (m, 1 H); 4.19 (t, J ¼ 6.6, 2 H); 3.94 (s, 3 H); 3.64 – 3.67 (m, 1 H); 3.58 (t, J ¼ 6.0, 2 H); 3.36 (s,
3 H); 3.28 – 3.33 (m, 1 H); 2.53 – 2.59 (m, 1 H); 1.98 – 2.18 (m, 8 H); 1.58 – 1.68 (m, 1 H); 1.01 (d, J ¼ 6.9,
3 H); 0.95 (d, J ¼ 6.9, 6 H); 0.89 (d, J ¼ 6.9, 3 H).
(3S,5S)-Dihydro-5-{(1S,3S)-1-hydroxy-3-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-4-
methylpentyl}-3-(1-methylethyl)furan-2(3H)-one (15). To a soln. of 14 (0.846 g, 1.878 mmol) in MeOH
(40 ml), Pd/C (21 mg) was added. The mixture was shaken under 57 psi of H2 for 67 h. Then, the mixture
was filtered through a pad of Celite, which was washed with AcOEt, then with MeOH. The combined
filtrate and washings were concentrated. FC (hexane/AcOEt 2 :1, then 1:1) yielded 15 (0.606 g, 74%).
FT-IR: 3413, 3015, 2960, 1982, 1758, 1514, 1466, 1218. 1H-NMR (CDCl3): 6.68 – 6.79 (m, 3 H); 4.16 – 4.21
(m, 1 H); 4.10 (t, J ¼ 6.6, 2 H); 3.84 (s, 3 H); 3.58 (t, J ¼ 6.0, 2 H); 3.36 (s, 3 H); 3.35 – 3.36 (m, 1 H); 2.48 –
2.58 (m, 3 H); 1.96 – 2.19 (m, 5 H); 1.72 – 1.90 (m, 3 H); 1.50 – 1.60 (m, 1 H); 1.25 – 1.31 (m, 1 H); 1.01 (d,
J ¼ 6.9, 3 H); 0.89 (d, J ¼ 6.9, 3 H); 0.86 – 0.90 (m, 6 H). 13C-NMR (CDCl3): 179.0; 148.3; 147.6; 121.2;
114.2; 111.6; 82.0; 72.3; 69.4; 66.1; 58.7; 56.0; 45.6; 41.5; 37.5; 33.8; 29.5; 29.0; 26.2; 20.3; 19.9; 18.4; 17.5.
(1S,3S)-3-[4-Methoxy-3-(3-methoxypropoxy)benzyl]-4-methyl-1-[(2S,4S)-tetrahydro-4-isopropyl-5-
oxo-furan-2-yl]pentyl Methanesulfonate (¼(3S,5S)-Dihydro-5-{(1S,3S)-3-{[4-methoxy-3-(3-methoxyprop-
oxy)phenyl]methyl}-4-methyl-1-[(methylsulfonyl)oxy]pentyl}-3-(1-methylethyl)furan-2(3H)-one; 16).
To a soln. of 15 (0.360 g, 0.826 mmol) in CH2Cl2 (15 ml) at ꢀ 108, Et3N (0.576 ml, 4.132 mmol) was
added, followed by a CH2Cl2 (5 ml) soln. of MsCl (0.195 ml, 2.479 mmol). The mixture was stirred at 08
for 2 h. The reaction was quenched by adding H2O, and the mixture was extracted with AcOEt. The
combined org. phase was dried (Na2SO4) and concentrated. FC (hexane/AcOEt 2 :1) yielded 16 (0.412 g,
100%). FT-IR: 3019, 2961, 1971, 1774, 1514, 1466, 1350, 1216, 1171, 1028. 1H-NMR (CDCl3): 6.70 – 6.84
(m, 3 H); 4.54 – 4.60 (m, 1 H); 4.33 – 4.40 (m, 1 H); 4.12 (t, J ¼ 6.0, 2 H); 3.84 (s, 3 H); 3.58 (t, J ¼ 6.3,
2 H); 3.36 (s, 3 H), 3.13 (s, 3 H); 2.44 – 2.59 (m, 3 H); 1.90 – 2.16 (m, 5 H); 1.69 – 1.86 (m, 3 H); 1.30 – 1.39
(m, 1 H); 1.02 (d, J ¼ 6.9, 3 H); 0.93 (d, J ¼ 6.9, 3 H); 0.85 – 0.95 (m, 6 H). 13C-NMR (CDCl3): 177.5;
148.4; 147.7; 132.9; 121.2; 114.2; 111.6; 82.8; 78.5; 69.4; 65.9; 58.6; 56.1; 44.8; 41.1; 39.1; 37.4; 31.3; 29.5;
28.9; 28.6; 26.4; 20.2; 20.0; 18.4; 16.9.
(3S,5S)-5-{(1R,3S)-1-Bromo-3-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-4-methylpentyl}-
dihydro-3-(1-methylethyl)furan-2(3H)-one (17). To a soln. of 16 (0.052 g, 0.104 mmol) in THF (8 ml),
LiBr (0.052 g, 0.60 mmol) was added. The mixture was heated to reflux for 23 h. The reaction was

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Helvetica Chimica Acta – Vol. 95 (2012)
quenched by adding H2O, and the mixture was extracted with AcOEt. The combined org. phase was dried
(Na2SO4) and concentrated. FC (hexane/AcOEt 2 :1) yielded 17 (0.029 g, 57%). FT-IR: 2960, 1963, 1774,
1589, 1514, 1466, 1259, 1139, 1028. 1H-NMR (CDCl3): 6.81 (d, J ¼ 8.1, 1 H); 6.68 – 6.74 (m, 2 H); 4.32 –
4.39 (m, 1 H), 4.13 (t, J ¼ 7.2, 2 H); 4.00 – 4.01 (m, 1 H); 3.86 (s, 3 H); 3.60 (t, J ¼ 6.0, 2 H); 3.38 (s, 3 H);
2.76 (dd, J ¼ 13.8, 4.2, 1 H); 2.59 – 2.67 (m, 1 H); 2.08 – 2.27 (m, 6 H); 1.79 – 1.98 (m, 3 H); 1.57 – 1.66 (m,
1 H); 0.86 – 1.05 (m, 12 H).
(3S,5S)-5-{(1S,3S)-1-Azido-3-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-4-methylpentyl}-
dihydro-3-(1-methylethyl)furan-2(3H)-one (18). To a soln. of 17 (0.029 g, 0.059 mmol) in DMF (5 ml),
NaN3 (0.038 g, 0.588 mmol) was added. The mixture was heated to 908 and stirred at 908 for 48 h. The
mixture was concentrated. Extractive workup (AcOEt, H2O) was followed by FC (hexane/AcOEt 2 :1):
18 (0.0096 g, 35%). FT-IR: 3019, 2961, 2111, 1965, 1770, 1514, 1216, 1027. 1H-NMR (CDCl3): 6.70 – 6.83
(m, 3 H); 4.25 – 4.28 (m, 1 H); 4.10 (t, J ¼ 6.3, 2 H); 3.84 (s, 3 H); 3.58 (t, J ¼ 6, 2 H); 3.36 (s, 3 H); 2.92 –
2.98 (m, 1 H); 2.56 – 2.65 (m, 2 H); 2.43 – 2.51 (m, 1 H); 1.90 – 2.19 (m, 5 H); 1.66 – 1.83 (m, 3 H); 1.31 –
1.42 (m, 1 H); 0.90 – 1.04 (m, 12 H).
(2S,4S,5S,7S)-N-(3-Amino-2,2-dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-[4-methoxy-
3-(3-methoxypropoxy)benzyl]-8-methylnonanamide (¼(aS,gS,dS,zS)-N-(3-Amino-2,2-dimethyl-3-oxo-
propyl)-d-azido-g-hydroxy-4-methoxy-3-(3-methoxypropoxy)-a,z-bis(1-methylethyl)benzeneoctan-
amide; 19). A mixture of 18 (0.0082 g, 0.018 mmol), 3-amino-2,2-dimethyl-propanamide (0.031 g,
0.267 mmol), and propanoic acid (4 mg, 0.053 mmol) was heated to 1208 without stirring for 1.5 h. The
mixture was cooled to r.t. Extractive workup (AcOEt, H2O) was followed by FC (AcOEt/EtOH 11:1):
19 (0.0089 g, 0.015 mmol, 87%). FT-IR: 3414, 3356, 3019, 2962, 2400, 2110, 1962, 1666, 1514, 1470, 1216.
1H-NMR (CDCl3): 6.72 – 6.82 (m, 3 H); 6.40 (t, J ¼ 6.3, 1 H); 6.00 (s, 1 H); 5.39 (s, 1 H); 4.13 (t, J ¼ 6.6,
2 H); 3.86 (s, 3 H); 3.60 (t, J ¼ 6.3, 2 H); 3.38 (s, 3 H); 3.32 – 3.45 (m, 3 H); 3.04 – 3.06 (m, 1 H); 2.88 – 2.92
(m, 1 H); 2.49 – 2.54 (m, 2 H); 2.06 – 2.16 (m, 3 H); 1.85 – 1.95 (m, 1 H); 1.54 – 1.79 (m, 5 H); 1.30 – 1.39
(m, 1 H); 1.25 (s, 6 H); 0.88 – 0.96 (m, 12 H).
(2S,4S,5S,7S)-5-Amino-N-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxy-2-isopropyl-7-[4-me-
thoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide (¼Aliskiren ¼ (aS,gS,dS,zS)-d-Amino-N-(3-
amino-2,2-dimethyl-3-oxopropyl)-g-hydroxy-4-methoxy-3-(3-methoxypropoxy)-a,z-bis(1-methylethyl)-
benzeneoctanamide; 20). To 19 (20 mg, 0.034 mmol) and MeOH (2.5 ml), Pd/C (10 mg) was added, and
the mixture was stirred under H2 (g) for 3 h at r.t. Then, the mixture was filtered through a pad of Celite,
which was washed with EtOH, then with MeOH. The combined filtrate and washings were concentrated.
FC (EtOH/Et2O 4 :1) yielded 20 (0.007 g, 38%). 1H-NMR (CD3OD): 6.75 – 6.87 (m, 3 H); 4.08 (t, J ¼ 6.3,
2 H); 3.82 (s, 3 H); 3.60 (t, J ¼ 6.3, 2 H); 3.31 – 3.37 (m, 5 H); 3.10 – 3.15 (m, 1 H); 2.43 – 2.54 (m, 3 H);
2.20 – 2.30 (m, 1 H); 2.04 (quint., J ¼ 6.3, 2 H); 1.60 – 1.82 (m, 4 H); 1.27 – 1.47 (m, 3 H); 1.20 (s, 6 H);
0.90 – 0.98 (m, 12 H).
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Received August 8, 2012