Formal total synthesis of the potent renin inhibitor aliskiren: Application of a SmI2-promoted acyl-like radical coupling

Article abstract of DOI:10.1021/jo060296c

A formal total synthesis of the potent renin inhibitor aliskiren is disclosed exploiting an alternative coupling strategy recently developed by this laboratory for the preparation of the hydroxyethylene isostere-based class of protease inhibitors. The thi

Full text of DOI:10.1021/jo060296c

Formal Total Synthesis of the Potent Renin Inhibitor Aliskiren:
Application of a SmI2-Promoted Acyl-like Radical Coupling
Karl B. Lindsay and Troels Skrydstrup*
Center for Insoluble Protein Structures, Department of Chemistry, UniVersity of Aarhus, Langelandsgade
140, 8000 Aarhus C, Denmark
ts@chem.au.dk
ReceiVed February 13, 2006
A formal total synthesis of the potent renin inhibitor aliskiren is disclosed exploiting an alternative coupling
strategy recently developed by this laboratory for the preparation of the hydroxyethylene isostere-based
class of protease inhibitors. The thioester derivative of the amino acid representing the C5-C9 fragment
of the aliskiren carbon skeleton underwent a carbon chain extension via a SmI2-promoted radical addition
to n-butyl acrylate. Introduction of the C3-isopropyl group with the correct relative configuration was
accomplished via stereoselective reduction of the obtained ketone with concomitant lactonization, followed
by an aldol reaction with acetone. Further functional group and protecting group manipulation culminated
in a formal total synthesis of aliskiren in 10 steps from the corresponding fully protected non-natural
amino acid.
Introduction
HIV (HIV protease),11 opportunistic fungi infections in AIDS
patients (secreted aspartic protease from Candida albicans),12
or neurodegenerative disorders such as Alzheimer’s disease (â-
and γ-secretase).13 Enormous efforts have therefore been
undertaken to develop selective inhibitors as therapeutic agents
for the treatment of disorders linked to the involvement of
aspartic proteases.14,15 As illustrated by compounds 1-4 in
Figure 1, the hydroxyethylene isostere constitutes an important
structural entity of many successful and potent aspartic protease
inhibitors,16-20 replacing the scissile bond in the specific
dipeptide portion of the substrate undergoing amide hydrolysis.
This subunit mimics the tetrahedral intermediate in the enzyme-
Aspartic proteases (aspartic endopeptidases) comprise one of
the four primary classes of peptide cleaving enzymes, exploiting
two aspartic acid residues for their catalytic activity with the
direct participation of a lytic water molecule.1-6 These enzymes
play an important role in the regulation of a variety of
physiological processes such as digestion (pepsin),7 the control
of blood pressure (plasma renin),8 and the degradation of
endocytosed peptides (lysosomal cathepsin D).9 Furthermore,
they are responsible for acute disease propagation caused either
by parasites such as malaria (plasmepsin),10 viruses, including
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10.1021/jo060296c CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/23/2006
4766
J. Org. Chem. 2006, 71, 4766-4777

Synthesis of the Potent Renin Inhibitor Aliskiren
FIGURE 1. Some prominent protease inhibitors featuring the hydroxyethylene isostere moiety.
mediated cleavage with the hydroxyl group interacting with the
aspartic acid side chains through hydrogen bonding.14,15
While renin represents a key player in the renin-angiotensin
system for controlling blood volume, arterial pressure, and
cardiac and vascular function, its manipulation also provides a
means for the therapeutic treatment of hypertension and heart
failure.21,22 Renin is secreted by the kidney in response to a
decrease in circulating volume and blood pressure and cleaves
the substrate angiotensinogen to form the inactive angiotensin
I. Angiotensin I is converted to the active angiotensin II by
angiotensin converting enzyme (ACE). Interestingly, the first
inhibitors containing a hydroxyethylene isostere reported were
developed in 1982 for the purpose of inhibiting renin.23 While
many drug candidates in the subsequent years were identified
displaying potent in vitro and in vivo activity, their application
as new antihypertensive agents was abandoned due to inadequate
oral bioavailability properties (low stability, poor solubility).24
Furthermore, compared to the ACE targeting drugs, renin
inhibitors require interaction with additional subsites for tight
binding resulting in the requirement of higher molecular weight
compounds and hence non-cost-effective syntheses. Neverthe-
less, in contrast to renin, ACE is implicated in alternative
pathways and its inhibition therefore results in side effects
(cough, angioneurotic edema).25
To improve the unfavorable pharmacokinetic behavior of
earlier peptide-like renin inhibitors, a combination of molecular
modeling and crystallographic structural analyses were em-
ployed by a team of Novartis chemists to design a new class of
hydroxyethylene-based renin inhibitors lacking the peptide back-
bone.18 Out of this intensive study, the nonpeptidic compound,
aliskiren (Figure 1), successfully emerged as a potent renin mod-
ulator, exhibiting sub-nanomolar binding affinity to human renin
and oral administration properties.26 This compound is now
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G. Chem. Biol. 2000, 7, 493.
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C.; Rasetti, V.; Rueger, H.; Goeschke, R.; Stutz, S.; Fuhrer, W.; Schilling,
W.; Rigollier, P.; Yamaguchi, Y.; Cumin, F.; Baum, H.-P.; Schnell, C. R.;
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hydroxyethylene isosteres for the inhibition of a variety of proteases, see
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4401. (b) Evans, B. E.; Rittle, K. E.; Homnick, C. F.; Springer, J. P.;
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J. Org. Chem, Vol. 71, No. 13, 2006 4767

Lindsay and Skrydstrup
FIGURE 2. Previous coupling strategies employed for the synthesis of aliskiren.
SCHEME 1. Example of a Coupling Reaction with SmI2
and 4-Pyridylthioesters
nearing completion of Phase III clinical studies and holds great
promise as the first marketable renin inhibitor. Since its dis-
covery a number of synthetic approaches to the preparation of
aliskiren or the generic structure represented by its tetrasubsti-
tuted 8-aryloctanoic acid amide framework have been under-
taken. The key bond disconnections and coupling reactions for
each of these syntheses are depicted in Figure 2. Three of these
originate from Novartis, of which two led by Maibaum27 and
Sandham28 rely on asymmetric enolate alkylations for the
installation of the appropriate alkyl appendages at C2 and C7
and an ensuing organometallic addition step to secure the
8-aryloctanoic acid backbone. An alternative approach from
Speedel Pharma exploits two asymmetric catalytic transforma-
tions and an Fe(III)-mediated C-C bond-forming reaction.29
From academia, Dondoni30 and Ma31 have separately reported
modified versions of the Maibaum and Sandham syntheses. A
conceptionally different route to the generic structure of aliskiren
was published by Hanessian and co-workers relying on the use
of L-pyroglutamate as a chiral template and exploiting internal
induction to install stereoselectively the required functionality.32
Herein, we report full details of our synthetic endeavors directed
to accessing aliskiren via an alternative coupling strategy which
assembles the carbon backbone of the hydroxyethylene isostere
unit in a unique two step protocol involving our recently dis-
closed SmI2-mediated radical addition reaction followed by a
simple diastereoselective reduction step.33-37 Our interest in
examining the generality of this synthetic approach to accessing
a variety of the hydroxyethylene-based class of protease inhib-
itors (Figure 1) coupled with the structural complexity of
aliskiren suggested this compound would represent a worthy
opponent to evaluate the efficacy and flexibility of the synthesis
plan.
Results and Discussion
Synthesis Plan. In 2003, we reported the ability of thioester-
functionalized amino acids to effectively undergo a samarium
diiodide promoted radical addition to activated alkenes such as
acrylamides and acrylates affording products akin to a formal
acyl radical addition (Scheme 1).33 As rapid decarbonylation
of acyl radical generated from amino acid precursors precedes
the radical addition step, this unexpected observation suggested
that an alternative mechanism involving a ketyl-like radical
anion is operating for the low-valent lanthanide-mediated C-C
bond-forming reactions. The γ-keto amides and esters generated
from this coupling step represent products of high synthetic
value requiring only a simple stereoselective reduction of the
ketone functionality in order to access the targeted hydroxy-
ethylene dipeptide isosteres. We have demonstrated the adapt-
ability of such a synthetic route to structures acquainted with
many aspartic protease inhibitors.35 For example, Scheme 1
illustrates rapid access to 9, a compound possessing a similar
structure to the γ-secretase inhibitor 4.33 This pivotal C-C bond
forming reaction therefore represents a potential key synthetic
step for accessing the entire carbon skeleton of aliskiren.
A truncated retrosynthetic analysis of aliskiren with the above
considerations is illustrated in Scheme 2. The C3-C4 bond of
(27) Rueger, H.; Stutz, S.; Goschke, R.; Spindler, F.; Maibaum, J.
Tetrahedron Lett. 2000, 41, 10085.
(28) Sandham, D. A.; Taylor, R. J.; Carey, J. S.; Fassler, A. Tetrahedron
Lett. 2000, 41, 10091.
(29) Herold, P.; Stutz, S. WO 02/08172, Jan 31, 2002.
(30) Dondoni, A.; De Lathauwer, G.; Perrone, D. Tetrahedron Lett. 2001,
42, 4819.
(31) Dong, H.; Zhang, Z.-L.; Huang, J.-H.; Ma, R.; Chen, S.-H.; Li, G.
Tetrahedron Lett. 2005, 46, 6337.
(32) Hanessian, S.; Claridge, S.; Johnstone, S. J. Org. Chem. 2002, 67,
4261.
(33) Blakskjær, P.; Høj, B.; Riber, D.; Skrydstrup, T. J. Am. Chem. Soc.
2003, 125, 4030.
(34) Mikkelsen, L. M.; Jensen, C. M.; Høj, B.; Blakskjær, P.; Skrydstrup,
T. Tetrahedron 2003, 59, 10541.
(35) Jensen, C. M.; Lindsay, K. B.; Taaning, R. H.; Karaffa, J.; Hansen,
A. M.; Skrydstrup, T. J. Am. Chem. Soc. 2005, 127, 6544.
(36) Jensen, C. M.; Lindsay, K. B.; Andreasen, P.; Skrydstrup, T. J. Org.
Chem. 2005, 70, 7512.
(37) For some recent reviews on the use of SmI2 in organic synthesis,
see: (a) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. ReV. 2004,
104, 3371. (b) Kagan, H. B. Tetrahedron 2003, 59, 10351. (c) Steel, P. G.
J. Chem. Soc., Perkin Trans. 1 2001, 2727. (d) Krief, A.; Laval, A.-M.
Chem. ReV. 1999, 99, 745. (e) Molander, G. A.; Harris, C. R. Tetrahedron
1998, 54, 3321. (f) Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96,
307.
4768 J. Org. Chem., Vol. 71, No. 13, 2006

Synthesis of the Potent Renin Inhibitor Aliskiren
SCHEME 2. Retrosynthetic Considerations of Aliskiren
SCHEME 3. Possible Approaches to Installing the r-Isopropyl Group
the 8-aryloctanoic acid skeleton was envisaged to be assembled
SCHEME 4. Approach I Model Study
in a highly convergent fashion by the addition of two fully
functionalized subunits, the acyl radical 10 and the acrylamide
11. Alternatively, an acrylate derivative could also operate as
the radical acceptor with the amide moiety installed later in the
synthesis. Placing our major disconnection at the common
hydroxyethylene unit should introduce flexibility into the
synthesis, which would in turn facilitate access to new ana-
logues. The acyl radical equivalent 10 required from this
disconnection could be prepared from the corresponding non-
natural amino acid, itself synthesized by asymmetric alkylation
of a chiral glycine equivalent 12 with the known alkyl bromide
13. The application of this non-natural amino acid was expected
to complement our earlier studies with naturally occurring amino
acids. Achieving high stereochemical control at C2 was
nevertheless a major concern which was addressed from the
outset of this synthetic project. In our earlier work with the
thioester addition reactions, the influence of R-methyl substitu-
tion on the acrylamide was examined, but 1,4-stereocontrol in
those cases was only modest.33 Although the steric bulk of the
isopropyl side group could reinforce any stereochemical prefer-
ences in the enolate protonation step (Scheme 3, approach I),
options were nevertheless required in the event of an unsuc-
cessful outcome such as low or incorrect selectivity. Theoreti-
cally, the stereoselective introduction of the C2-alkyl appendage
could also be accomplished at two other stages, namely during
the radical addition step (approach II) through the trapping of
the putative enolate intermediate resulting from the second
electron transfer or after (approach III) via internal induction
from a cyclic lactone enolate intermediate.38
procedures39 and was converted to acrylamide 17 via basic
hydrolysis followed by an EDCI promoted amide coupling with
n-butylamine. The key coupling reactions were then carried out
according to earlier work by subjecting a THF solution of the
acrylate or acrylamide combined with the 4-pyridylthioester of
Cbz-protected phenylalanine 5 (1.5 equiv) to 3.3 equiv of SmI2
for 3 days at -78 °C. Regrettably, concerns about the stereo-
selectivity of this reaction were unwarranted as the coupling
products were not observed. Instead significant amounts of
unreacted starting materials were obtained together with a
(38) Numerous reports have illustrated the use of lactones as a precursor
to dipeptide hydroxyethylene isosteres. For representative examples, see:
(a) Fray, A. H.; Kaye, R. L.; Kleinman, E. F. J. Org. Chem. 1986, 51,
4828. (b) DeCamp, A. E.; Kawaguchi, A. T.; Volante, R. P.; Shinkai, I.
Tetrahedron Lett. 1991, 32, 1867. (c) Hoffman, R. V.; Kim, H.-O.
Tetrahedron Lett. 1992, 33, 3579. (d) Dondoni, A.; Perrone, D.; Semola,
M. T. J. Org. Chem. 1995, 60, 7927. (e) Hanessian, S.; Abad-Grillo, T.;
McNaughton-Smith, G. Tetrahedron 1997, 53, 6281. (f) Aguilar, N.;
Moyano, A.; Perica`s, M. A.; Riera, A. J. Org. Chem. 1998, 63, 3560. (g)
Trost, B. M.; Rhe, Y. H. J. Am. Chem. Soc. 1999, 121, 11680. (h) Fukuzawa,
S.-i.; Miura, M.; Saitoh, T. J. Org. Chem. 2003, 68, 2042. (i) Urban, F. J.;
Jasys, V. J. Org. Proc. Res. DeV. 2004, 8, 169.
Model Studies. The model study for approach I, whereby
the isopropyl side chain had already been installed prior to the
coupling reaction, is shown in Scheme 4. Acrylate 16 was
prepared in two steps from n-butyl acetoacetate using published
(39) Lee, H.-S.; Park, J.-S.; Kim, B. M.; Gellman, S. H. J. Org. Chem.
2003, 68, 1575.
J. Org. Chem, Vol. 71, No. 13, 2006 4769

Lindsay and Skrydstrup
the hydroxyethylene isosteres.20,38 To this end, we next initiated
a short study regarding the stereoselective reduction of γ-keto
esters 24a-e with concomitant cyclization to γ-butyrolactones
as shown in Table 1. A series of γ-keto esters were synthesized
as recently reported by us,36 via reaction of the 4-pyridylth-
ioesters of Cbz-protected amino acids 5 with SmI2, in the
presence of tert-butyl alcohol and either methyl or n-butyl
acrylate at -78 °C in yields ranging from 40 to 80%.
SCHEME 5. Approach II Model Study
Ketone reduction with (S)-Alpine Hydride42a (entries 1, 3, 4,
5, and 7) generally proceeded rapidly at -78 °C in THF
affording excellent stereoselectivity for the (S)-stereoisomer, and
the intermediates then slowly reacted further overnight at
-78 °C to give the desired lactones 26. Generally, the methyl
esters (entries 3, 5, and 7) underwent conversion to the lactone
faster than the corresponding n-butyl esters (entries 1 and 4).
To gain access to the complementary (R)-stereoisomer, Luche
reduction conditions (NaBH4, CeCl3‚7H2O, MeOH) were also
examined (entries 2, 6, and 8).42b The selectivities were lower
and, with the exception of the γ-ketone derived from alanine
(entry 6), reactions ceased at the alcohol stage. In all cases the
intermediate alcohol could be separated from the more polar
lactone upon purification by column chromatography. Con-
version of any intermediate alcohols 25 to the desired lactones
could be readily promoted by treatment with NaH in THF in
excellent yields (entries 2 and 6). Assignment of stereochemistry
is based on the extensive reduction results obtained by other
researchers.38c, 42
10-20% yield of the aldehyde 20. Increasing the number of
equivalents of the radical acceptor or the reaction time did not
improve the outcome.40 Thus, the normal addition pathway
appears to be critically slowed by steric hindrance of the
isopropyl group. As such, the proposed ketyl radical intermediate
may resort to alternative routes including either a hydrogen
abstraction step or reduction by SmI2 followed by protonation
with the formation of the aldehyde as the end result.
Turning to approach II (Scheme 5), we explored the pos-
sibility of introducing the isopropyl side chain during the
coupling reaction by trapping the proposed samarium(III) enolate
intermediate with acetone followed by a deoxygenation step.
Such sequential radical-anionic reactions promoted by SmI2 have
literature precedence including the use of acetone as the coupling
reagent.37 Hence, attempts were performed to couple the
thioester 7 to n-butyl acrylamide in the presence of 5 equiv of
acetone. Although the radical reactions proceeded as planned,
quite unexpectedly none of the desired alkylated product could
be isolated, and only the unalkylated product 21 was formed.
Internal protonation from the amide group was likely the culprit,
yet we have previously trapped samarium(III) glycine enolates
with either ketones or aldehydes without major intervention of
this protonation pathway.41 In stark contrast, when n-butyl
acrylate was used the enolate intermediate could be trapped,
prompting the suggestion that an internal proton transfer was
indeed the problem with the reactions featuring the acrylamide.
The resulting alkylated product 22 undergoes ring closure and
was isolated as its hemiacetal form 23 in a good 74% yield.
This structure represents a ring constrained γ-hydroxyester and
may therefore be a useful precursor to a new class of potential
protease inhibitors. It was interesting to note that only two
isomers dominated from the possible four, though unfortunately
we have been unable to establish which of these has formed,
due to problems regarding separation of the isomers. Attempts
to react hemiacetal 23 further by accessing its ketone form were
unsuccessful. For example, subjecting the hemiacetal to reduc-
tion in order to produce the corresponding diol was unsuccessful
when using either (S)-Alpine Hydride or NaBH4. We attribute
the low reactivity of 23 to a gem-dimethyl effect bestowing a
marked stability to the hemiacetal form. Therefore, we were
prompted to explore approach III, introducing the isopropyl
group at a later stage in the synthesis.
With these successful reduction studies terminated, we then
proceeded to complete the model study as planned in approach
III (Scheme 6). Introduction of the C2-isopropyl group pro-
ceeded by deprotonation of lactone 26a with LiHMDS, and then
reaction with excess acetone generated the alkylated product
27 in excellent yield and diastereoselectivity (91%, dr 20:1),
which is expected to favor the least hindered side of the lactone
ring affording the trans product.38e Removal of the unwanted
hydroxyl group was achieved by its initial elimination, easily
accomplished by reaction with PCl5, giving an 8:1 mixture of
regioisomers in favor of the terminal isomer 28. Finally,
completion of the hydroxyethylene isostere core was realized,
by first ring opening the lactone using n-butylamine and
20d,43
AlMe3
providing amide 29 in a 55% yield, followed by a
simultaneous reduction of the double bond and removal of the
Cbz protection group affording 30 upon subjection to hydro-
genation conditions. The unoptimized yield of 55% for the ring
opening step, was attributed to two undesired, though not
surprising, competing reactions. Evidence of rearrangement of
the double bond into conjugation with the amide carbonyl, and
of further reaction of the product alcohol with the Cbz protecting
group furnishing an oxazolidinone, were both observed within
the minor byproducts formed under the conditions required for
the reaction.
(40) We have previously observed the formation of aldehyde products
in attempts to couple amino acid thioesters with more sterically demanding
side chains (ref 36).
(41) (a) Ricci, M.; Madariaga, L.; Skrydstrup, T. Angew. Chem., Int.
Ed. 2000, 39, 242. (b) Ricci, M.; Blakskjær, P.; Skrydstrup, T. J. Am. Chem.
Soc. 2000, 122, 12413. (c) Blakskjær, P.; Gavrila, A.; Andersen, L.;
Skrydstrup, T. Tetrahedron Lett. 2004, 45, 9091.
In approach III, a diastereoselective ketone reduction step is
required with concomitant lactone formation. Other researchers
have demonstrated the ability of chiral γ-butyrolactones to
undergo stereoselective R-alkylation with good 1,4-asymmetric
induction,38 making these compounds common precursors to
(42) Asymmetric reduction of R-amino ketones is comprehensively
covered in: (a) Våbenø, J.; Brisander, M.; Lejon, T.; Luthman, K. J. Org.
Chem. 2002, 67, 9186. (b) Hoffman, R. V.; Maslouh, N.; Cervantes-Lee,
F.; J. Org. Chem. 2002, 67, 1045.
(43) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 18,
4171.
4770 J. Org. Chem., Vol. 71, No. 13, 2006

Synthesis of the Potent Renin Inhibitor Aliskiren
TABLE 1. Ketone Reduction Studies
entry
substrate
reductant
S/R
alcohol (yield, %)
lactone (yield, %)
1
2
3
4
5
6
7
8
24a
24a
24b
24c
24d
24d
24e
24e
(S)-Alpine Hydride
NaBH4, CeCl3
(S)-Alpine Hydride
(S)-Alpine Hydride
(S)-Alpine Hydride
NaBH4, CeCl3
10:1
1:4
10:1
10:1
10:1
1:4
25a (19)
25a (13), 25b (81)
26a (79)
26b (91)a
26a (95)
25c (15)
26c (59)b
26c (93)
26c + 26d (87)
(S)-Alpine Hydride
NaBH4, CeCl3
10:1
2:5
26e (88)
25e + 25f (84)
26f (66),a 26e (25)a
a Lactone derived from reaction of alcohol 25 with NaH. b Unoptimized yield.
SCHEME 6. Approach III Model Studya
repeating Myers’ chemistry was effective in our hands with
reactive bromides such as BnBr, bromide 13 was recovered
unreacted under identical conditions even after prolonged
reaction times. When the corresponding iodide 35 was exam-
ined, alkylation did proceed in 38% yield; however, the product
32 was difficult to purify which subsequently interfered with
the establishment of the stereoselectivity of this reaction.
Furthermore, reduction of the iodide was a major competing
reaction furnishing the corresponding alkane in 56% yield. As
an alternative, the cyclic glycine auxiliary 33 developed by
Williams et al.46 was also studied. Once again, good results
could only be obtained when using reactive electrophiles. When
unactivated electrophiles, such as bromide 13, iodide 35, or
triflate 36 were used, the coupling step proved unrewarding.
Thus we reasoned it was necessary to apply the Scho¨llkopf
methodology47 as reported by the Novartis group,44 suspecting
that they may have reached this conclusion in a similar manner
(Scheme 8). Coupling of the bis-lactim 37 with bromide 13 then
afforded 38 in an excellent yield (90%) and with a high
diastereomeric ratio (98:2). Acidic hydrolysis of the bis-lactim
auxiliary followed by Cbz protection under standard conditions
afforded the fully protected nonnatural amino acid 40.48 Ester
hydrolysis provided the free acid 41, which was then coupled
with 4-mercaptopyridine using EDCI to give the required
thioester 42 in excellent yield, with no evidence of any
R-epimerization. Reaction of the thioester with either methyl
or n-butyl acrylate in the presence of SmI2 and t-BuOH
proceeded slowly, but gave the methyl and butyl γ-keto esters
43 and 44 respectively in satisfactory yields of 60-70% after
a Reagents and conditions: (a) LiHMDS, THF, -78 °C, 2 h, then acetone,
91%, dr ) 20:1; (b) PCl5, CH2Cl2, -78 °C, 88%, term/conj ) 8:1; (c)
n-BuNH2, Al(CH3)3, CH2Cl2, 20 °C, 55%; (d) Pd/C/H2, EtOH, 94%.
SCHEME 7. Asymmetric Alkylation of Glycine Enolates
(44) Goeschke, R.; Stutz, S.; Heinzelmann, W.; Maibaum, J. HelV. Chim.
Acta 2003, 86, 2848.
(45) (a) Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung, D. W. J. Am.
Chem. Soc. 1997, 119, 656. (b) Myers, A. G.; Yang, B. H.; Chen, H.;
McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997,
119, 6496. (c) Myers, A. G.; Schnider, P.; Kwon, S.; Kung, D. W. J. Org.
Chem. 1999, 64, 3322.
(46) (a) Williams, R. M.; Im, M. N. J. Am. Chem. Soc. 1991, 113, 9276.
(b) Williams, R. M. Aldrichim. Acta 1992, 25, 15.
(47) (a) Schoellkopf, U.; Westphalen, K. O.; Schroeder, J.; Horn, K.
Liebigs Ann. Chem. 1988, 781. (b) Schoellkopf, U.; Groth, U.; Deng, C.
Angew. Chem., Int. Ed. Engl. 1981, 20, 798. (c) Bull, S. D.; Davies, S. G.;
Moss, W. O. Tetrahedron: Asymmetry 1998, 9, 321.
Formal Total Synthesis of Aliskiren. With our successful
model study in hand, we next moved toward the total synthesis
of aliskiren. For this the corresponding non-natural amino acid
was required, envisaged to be prepared by asymmetric alkylation
of a chiral glycine equivalent with the bromide 13 previously
prepared by Maibaum and co-workers in eight steps.44 Although
the same researchers converted the bromide to the requisite
amino acid exploiting Scho¨llkopf’s methodology, we chose to
initially examine other perhaps more direct alternatives described
by Williams and Myers (Scheme 7).
(48) Previous experience within this group has shown that the Cbz group
is sterically better tolerated in the SmI2 coupling reaction than the
corresponding Boc group thus dictating its choice here (refs 33 and 36).
Initially, the pseudoephedrine amide of glycine 31 was reacted
according to procedures outlined by Myers et al.45 While
J. Org. Chem, Vol. 71, No. 13, 2006 4771

Lindsay and Skrydstrup
SCHEME 8. Synthesis of Advanced Lactone Intermediatea
a Reagents and conditions: (a) n-BuLi, THF, -75 °C, then 9 -75 to -18 °C, 90%; (b) HCl, H2O, CH3CN, 99%; (c) CbzCl, pyridine, CH2Cl2, 88%; (d)
NaOH (2 M), THF, MeOH, 100%; (e) EDCI, 4-mercaptopyridine, CH2Cl2, 0 °C, 97%; (f) SmI2, t-BuOH, -78 °C, 6 d, methyl acrylate, 67%, or butyl
acrylate, 60%; (g) (S)-Alpine Hydride, THF -78 °C, 91%, dr ) 4:1; (h) LiHMDS, THF, -78 °C, 2 h, then acetone, 97%, dr ) 5:1; (i) PCl5, CH2Cl2, -78
°C, 99%, term/conj ) 8:1.
6 days at -78 °C. It was gratifying that such a large amino
acid side chain was tolerated in this radical coupling step, as
we earlier had found that sometimes even small steric hindrances
(such as with the 4-pyridylthioesters of Cbz-valine or Boc-leu-
cine, for example) can halt the reaction completely.36 Reduction
of compound 43 to lactone 45 using (S)-Alpine Hydride
proceeded in high yield; however, the diastereoselectivity was
somewhat lower (4:1) when compared with the model study
starting from phenylalanine, which we have tentatively assigned
a (5S) stereochemistry based on earlier results. This is consistent
with a mismatched case, where the substrate directs reduction
toward the undesired face and the larger side chain exacerbates
that effect. Nevertheless, separation of isomers could be achieved
by careful column chromatography on silica gel. Alkylation with
LiHMDS and acetone as before gave 46 in excellent yield, but
with a decreased selectivity (5:1) as an inseparable mixture of
isomers. Finally elimination of the tertiary alcohol with PCl5
as described above supplied us with the advanced intermediate
47 displaying a selectivity of 8:1 for the terminal/conjugated
regioisomers. Completion of the formal total synthesis of 2 is
illustrated in Scheme 9. Attempts to ring open lactone 47 directly
with amines as per the model study were met with failure,
leading instead to rearrangement of the double bond into
conjugation and/or product decomposition. For this reason, the
same lactone was subjected to Pd/C under H2 which both
reduced the double bond and removed the Cbz protecting group
providing the free amine 48. Reprotection of the amine as the
more stable Boc carbamate then gave a readily separable 4:1
mixture of lactones 49 and 54. The major isomer 49 responded
to ring opening conditions more predictably, for example
reaction with n-butylamine and AlMe3 in dichloromethane at
20 °C produced the simplified aliskiren analogue 50 in a 58%
yield. Lactone 49 has been previously converted to aliskiren
by Ma et al.31 via lactone amidation and deprotection thereby
completing a formal total synthesis of the renin inhibitor. Amine
48 is also readily transformed into the known lactone 52 through
a reductive alkylation with benzaldehyde and NaBH4. This same
lactone represents a late stage intermediate in the total synthesis
of the aliskiren reported by Dondoni et al.30
Access to the C2-epimer of the simple aliskiren analogue 50
was likewise possible by base-catalyzed isomerization of the
double bond of lactone 47 into conjugation. The corresponding
conjugated alkene in 51 can thus be reduced selectively38e
affording lactone 54 after Boc protection, with inverted stereo-
chemistry at C2. Ring opening with n-butylamine and AlMe3
proceeded as with the lactone 49 generating C2-epimer 55.
Conclusions
We have achieved our objective of applying a SmI2-promoted
acyl-like radical addition reaction between an amino acid
thioester and an activated alkene as a key step to the formal
synthesis of the potent renin inhibitor, aliskiren. Although this
synthesis does not compete with the industrial preparation of
aliskiren, it does provide a relevant example on the use of this
coupling methodology for accessing an important intermediate
in the synthesis of hydroxyethylene isosteres, the functionalized
γ-lactone, in only two steps from an amino acid thioester. Work
is now underway to identify conditions which permit the radical-
based C-C bond-forming step to be performed with R-branched
acrylates and acrylamides as well as studying stereochemical
issues. A successful venture in this direction would provide a
rapid and general approach to this class of hydroxyethylene
dipeptide isosteres.
Experimental Section
Butyl 5-((1S)-1-Benzyloxycarbonylamino-2-phenylethyl)-5-
hydroxy-2,2-dimethyltetrahydrofurancarboxylate (23). The
thioester 7 (177 mg, 0.45 mmol) was dissolved in anhydrous THF
4772 J. Org. Chem., Vol. 71, No. 13, 2006

Synthesis of the Potent Renin Inhibitor Aliskiren
SCHEME 9. Formal Total Synthesis of Aliskirena
a Reagents and conditions: (a) Pd/C/H2, EtOH, 99%; (b) Boc2O, NEt3, THF, 83%; (c) AlMe3, n-BuNH2, CH2Cl2, 58%; (d) pyridine, NEt3, 80 °C, CH2Cl2,
89%; (e) Pd/C/H2, EtOH, 90%, dr ) 10:1; (f) Boc2O, NEt3, THF, 81%; (g) AlMe3, n-BuNH2, CH2Cl2, 48%.
(5 mL) and the flask flushed with argon for 10 min. n-Butyl acrylate
(144 µL, 1.35 mmol) and acetone (165 µL, 2.25 mmol) were added,
and then the mixture was cooled to -78 °C before a 0.1 M solution
of SmI2 (15 mL, 1.50 mmol) was added via syringe. The mixture
was stirred at -78 °C for 2 d, the flask flushed with O2 before
satd NH4Cl solution (2 mL) was added, and the mixture warmed
to rt. The mixture was poured into 0.5 M HCl (40 mL) and extracted
with EtOAc (3 × 20 mL). The combined organics were dried
(MgSO4), filtered, and evaporated in vacuo. The pure product was
obtained by column chromatography (10-50% EtOAc in pentane
as eluant), which gave 23 (Rf ) 0.50-0.60, 30% EtOAc in pentane)
(156 mg, 0.332 mmol, 74%) as a colorless oil as an inseparable
1:1 mixture of diastereoisomers: 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.10-7.40 (m, 10H), 5.87 (br s, 1/2H), 5.56 (br s, 1/2H), 4.85-
5.09 (m, 3H), 3.93-4.18 (m, 3H), 3.10-3.37 (m, 2H), 2.09-2.89
(m, 3H), (m, 2H), 1.67-1.60 (m, 2H), 1.54 (s, 11/2H), 1.26-1.43
(m, 2H), 1.35 (s, 11/2H), 1.35 (s, 11/2H), 1.10 (s, 11/2H), 0.95 (t, J
) 7.2 Hz, 11/2H), 0.94 (t, J ) 7.2 Hz, 11/2H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 176.3, 171.6, 156.4, 138.9-126.2 (multiple peaks,
24C), 106.8, 105.4, 85.0, 84.2, 66.8, 66.5, 65.7, 64.8, 60.7, 59.2,
52.9, 52.3, 39.9, 38.5, 37.9, 37.1, 30.9, 30.8, 30.7, 30.6, 25.9, 24.4,
19.3, 19.2, 13.8, 13.7; HRMS C27H35NO6 [M + Na+] calcd
492.2362, found 492.2362.
Phenylmethyl [(1S)-2-Phenyl-1-[(2S)-tetrahydro-5-oxo-2-fura-
nyl]ethyl]carbamate (26a).38c The γ-keto ester 24a (40 mg, 0.0972
mmol) was dissolved in THF (10 mL), and then the solution was
cooled to -78 °C before the addition of (S)-Alpine Hydride (0.5
mL, 0.25 mmol, 0.5 M in THF). The mixture was stirred at -78
°C for 3 h, en satd NH4Cl solution (5 mL) was added, and the
mixture was warmed to rt before being poured into water (30 mL)
and extracted with EtOAc (3 × 15 mL). The combined organics
were dried (MgSO4), filtered, and evaporated in vacuo. The pure
product was obtained by column chromatography (10-40% EtOAc
in pentane as eluant), which gave lactone 26a (Rf ) 0.45, 35%
EtOAc in pentane) (26 mg, 0.0766 mmol, 79%) as an oil, and the
intermediate alcohol 25a (Rf ) 0.60, 35% EtOAc in pentane) (8
mg, 0.019 mmol, 20%) as a white solid. 26a: 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.20-7.40 (m, 10H), 5.07 (AB system, J ) 12.0
Hz, 2H), 4.98 (d, J ) 9.6 Hz, 1H), 4.48 (t, J ) 7.2 Hz, 1H), 4.08
(q, J ) 8.8 Hz, 1H), 2.95 (AB system d, J ) 15.2, 7.2 Hz, 2H),
2.47 (t, J ) 8.4 Hz, 2H), 2.03-2.18 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 177.0, 156.5, 136.9, 136.2, 129.3 (2C), 128.7 (2C),
128.5 (2C), 128.1, 127.9 (2C), 126.8, 79.7, 67.0, 54.7, 39.2, 28.6,
24.0; HRMS C20H21NO4 [M + Na+] calcd 362.1368, found
362.1361.
Phenylmethyl [(1S)-2-Phenyl-1-[(2S,4R)-tetrahydro-4-(1-hy-
droxy-1-methylethyl)-5-oxo-2-furanyl]ethyl]carbamate (27). The
lactone 26a (59 mg, 0.174 mmol) was dissolved in THF (7.5 mL)
and the mixture cooled to -78 °C. LiHMDS (0.40 mL, 0.40 mmol,
1.0 M in hexanes) was added and the mixture stirred for 80 min
before the addition of acetone (0.15 mL, 2.04 mmol). The mixture
was stirred for an additional 90 min, then satd NH4Cl (aq) (5 mL)
was added and the mixture allowed to warm to rt. The mixture
was poured into water (30 mL) and extracted with EtOAc (3 × 15
mL), and then the combined organics were dried (Na2SO4), filtered,
and evaporated in vacuo. The pure product was obtained by column
chromatography (5:5:2-0:1:1 pentane/CH2Cl2/Et2O as eluant),
which gave compound 27 (Rf ) 0.20, 1:1:1 pentane/CH2Cl2/Et2O)
(60 mg, 0.151 mmol, 87%) as an oil: 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.18-7.40 (m, 10H), 5.05 (s, 2H), 5.00 (d, J ) 9.6 Hz,
1H), 4.50 (dd, J ) 8.4, 4.4 Hz, 1H), 4.05-4.15 (m, 1H), 3.08 (br
s, 1H), 2.91 (d, J ) 8.0 Hz, 2H), 2.66 (dd, J ) 10.4, 8.0 Hz, 1H),
2.27 (td, J ) 12.4, 4.8 Hz, 1H), 2.05-2.17 (m, 1H), 1.24 (s, 3H),
1.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 178.6, 156.6,
136.8, 136.1, 129.2 (2C), 128.7 (2C), 128.5 (2C), 128.2, 127.9 (2C),
126.8, 78.3, 71.4, 67.0, 55.7, 49.9, 38.8, 27.6, 27.2, 22.8; HRMS
C23H27NO5 [M + Na+] calcd 420.1787, found 420.1782.
Phenylmethyl [(1S)-2-Phenyl-1-[(2S,4R)-tetrahydro-4-isopro-
penyl-5-oxo-2-furanyl]ethyl]carbamate (28). The alcohol 27 (55
mg, 0.138 mmol) was dissolved in CH2Cl2 (10 mL) and the mixture
cooled to -78 °C before PCl5 (70 mg, 0.336 mmol) in CH2Cl2 (3
mL) was added via syringe. The mixture was stirred at -78 °C for
40 min, satd NaHCO3(aq) (5 mL) was added, and the mixture was
allowed to warm to rt. The mixture was poured into water (30 mL)
and extracted with CH2Cl2 (3 × 15 mL), and then the combined
organic portions were dried (Na2SO4), filtered, and evaporated in
vacuo. The pure product was obtained by column chromatography
(10-20% EtOAc in pentane as eluant), which gave compound 28
(Rf ) 0.50, 20% EtOAc in pentane) (46 mg, 0.121 mmol, 88%) as
white solid. An 8:1 mixture of terminal:conjugated regioisomers
J. Org. Chem, Vol. 71, No. 13, 2006 4773

Lindsay and Skrydstrup
1
was evident from H NMR spectroscopy: 1H NMR (400 MHz,
mL). The combined organic portions were dried (MgSO4), filtered
and evaporated, which gave iodide 35 (86 mg, 0.212 mmol, 95%)
as a white solid requiring no further purification: 1H NMR (400
MHz, CDCl3) δ (ppm) 6.71 (d, J ) 8.4 Hz, 1H), 6.68 (d, J ) 1.6
Hz, 1H), 6.66 (dd, J ) 8.4, 1.6 Hz, 1H), 4.03 (t, J ) 6.4 Hz, 2H),
3.76 (s, 3H), 3.50 (t, J ) 6.5 Hz, 2H), 3.28 (s, 3H), 3.14 (dd, J )
10.0, 4.8 Hz, 1H), 3.02 (dd, J ) 10.0, 4.4 Hz, 1H), 2.69 (dd, J )
13.6, 4.8 Hz, 1H), 2.28 (dd, J ) 13.6, 9.6 Hz, 1H), 2.02 (quin., J
) 6.4 Hz, 2H), 1.64 (oct., J ) 6.8 Hz, 1H), 1.07 (dddt, J ) 9.6,
6.8, 4.8, 4.8 Hz, 1H), 0.93 (d, J ) 6.8 Hz, 3H), 0.87 (d, J ) 6.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 148.3, 147.8, 132.9,
121.1, 114.1, 111.8, 69.3, 66.0, 58.6, 56.0, 47.5, 36.6, 30.5, 29.5,
19.8, 19.5, 14.3; HRMS C17H27O3I [M + Na+] calcd 429.0903,
found 429.0906.
Methyl (2S,4S)-2-[[(Phenylmethoxy)carbonyl]amino]-4-meth-
oxy-3-(3-methoxypropoxy)-γ-(1-methylethyl)benzene pentanoate
(40). The free amine 3944 (2.043 g, 5.56 mmol) was dissolved in
CH2Cl2 (35 mL), and then benzyl chloroformate (1.65 mL, 11.59
mmol) was added. Pyridine (0.94 mL) was then added carefully
(modest exotherm), before the mixture was stirred at rt for 2 h.
The mixture was poured into 0.5 M HCl (100 mL) and extracted
with CH2Cl2 (3 × 30 mL). The combined organic portions were
dried (MgSO4), filtered, and evaporated in vacuo to give an oil.
Pure product was obtained by column chromatography (increasing
polarity from 10% to 40% EtOAc in pentane as eluant), which gave
compound 40 (Rf ) 0.45, 35% EtOAc in pentane) (2.468 g, 4.92
mmol, 89%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.25-7.35 (m, 5H), 6.73-6.77 (m, 2H), 6.66 (d, J ) 7.6
Hz, 1H), 5.26 (d, J ) 6.4 Hz, 1H), 5.10 (s, 2H), 4.41 (app q, J )
7.2 Hz, 1H), 4.09 (t, J ) 6,4 Hz, 2H), 3.81 (s, 3H), 3.69 (s, 3H),
3.55 (t, J ) 6.4 Hz, 2H), 3.31 (s, 3H), 2.60 (dd, J ) 13.6, 4.8 Hz,
1H), 2.46 (dd, J ) 13.6, 7.2 Hz, 1H), 2.0 (p, J ) 6.4 Hz, 2H), 1.71
(h, J ) 6.4 Hz, 1H), 1.56-1.66 (m, 3H), 0.84 (d, J ) 6.8 Hz, 3H),
0.82 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm)
173.2, 155.9, 148.1, 147.5, 136.2, 133.4, 128.3 (2C), 127.9, 127.8
(2C), 121.1, 114.3, 111.6, 69.2, 66.7, 65.8, 58.4, 55.9, 52.3, 52.1,
41.8, 36.4, 33.1, 29.5, 27.8, 19.7, 171.1; HRMS C28H39NO7 [M +
Na+] calcd 524.2624, found 524.2603.
(2S,4S)-2-[[(Phenylmethoxy)carbonyl]amino]-4-methoxy-3-(3-
methoxypropoxy)-γ-(1-methylethyl)benzenepentanoic Acid (41).
The methyl ester 40 (273 mg, 0.544 mmol) was dissolved in THF
(5.6 mL), and then MeOH (5.6 mL) and 2 M NaOH solution (0.7
mL) were added. The mixture was stirred at rt for 3.5 h and then
poured into 0.2 M HCl (40 mL) and extracted with CH2Cl2 (3 ×
15 mL). The combined organic portions were dried (MgSO4),
filtered, and evaporated in vacuo giving the crude 41 (264 mg, 0.541
mmol, 99%) as a colorless gum that required no further purifica-
tion: 1H NMR (400 MHz, CDCl3) δ (ppm) 8.95 (br s, 1H), 7.25-
7.36 (m, 5H), 6.65-6.80 (m, 3H), 5.33 (d, J ) 8.8 Hz, 1H), 5.11
(s, 5H), 4.40 (td, J ) 8.8, 5.2 Hz, 1H), 4.04-4.15 (m, 2H), 3.81
(s, 3H), 3.58 (t, J ) 6.4 Hz, 2H), 3.33 (s, 3H), 2.60 (dd, J ) 13.6,
5.2 Hz, 1H), 2.48 (dd, J ) 13.6, 7.2 Hz, 1H), 2.07 (p, J ) 6.4 Hz,
2H), 1.58-1.80 (m, 4H), 0.85 (d, J ) 7.2 Hz, 3H), 0.83 (d, J )
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 176.2, 156.0,
148.1, 147.7, 136.2, 133.4, 128.5 (2C), 128.1 (2C), 127.9, 121.6,
114.4, 111.7, 69.4, 66.9, 65.9, 58.4, 56.0, 52.3, 41.8, 36.2, 33.4,
29.2, 28.2, 19.5, 17.8; HRMS C27H37NO7 [M + Na+] calcd
510.2468, found 510.2468.
Pyridin-4-yl (2S,4S)-2-[[(Phenylmethoxy)carbonyl]amino]-4-
methoxy-3-(3-methoxypropoxy)-γ-(1-methylethyl)benzenepen-
tanethioate (42). The acid 41 (264 mg, 0.541 mmol) was dissolved
in CH2Cl2 (10 mL), and then the solution cooled to 0 °C before
mercaptopyridine (79 mg, 0.707 mmol) and EDCI (156 mg, 0.816
mmol) were added. The mixture was stirred at 0 °C for 3.5 h, and
then the mixture was poured into water (40 mL) and extracted with
CH2Cl2 (3 × 20 mL). The combined organic portions were dried
(MgSO4), filtered, and evaporated in vacuo. The pure product was
obtained by column chromatography (50-100% EtOAc in pentane
as eluant) which gave compound 42 (Rf ) 0.25, 50% EtOAc in
CDCl3) δ (ppm) terminal regioisomer 7.15-7.38 (m, 10H), 5.07
(s, 2H), 4.93 (s, 1H), 4.90 (br s, 1H), 4.82 (s, 1H), 4.52 (t, J ) 7.2
Hz, 1H), 4.10 (q, J ) 8.4 Hz, 1H), 3.24 (dd, J ) 10.0, 5.6 Hz,
1H), 2.94 (d, J ) 7.6 Hz, 2H), 2.28-2.38 (m, 1H), 2.10-2.22 (m,
1H), 1.76 (s, 3H) conjugated regioisomer inter alia 2.21 (s, 3H),
1.61 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 176.7, 156.5,
140.1, 136.9, 136.2, 129.2 (2C), 128.7 (2C), 128.5 (2C), 128.2,
127.9 (2C), 126.8, 114.0, 78.4, 67.0, 55.0, 47.6, 39.2, 29.8, 20.6;
HRMS C23H25NO4 [M + Na+] calcd 402.1681, found 402.1670.
(2R,4S,5S)-(1-Methyl-2-ethenyl)hydroxy[(phenylmethoxy)-
carbonyl]amino-6-phenylhexanoic Acid N-Butylamide (29). n-
Butylamine was dissolved in CH2Cl2 (2 mL), and then trimeth-
ylaluminum (0.4 mL, 0.80 mmol) was added. The mixture was
stirred at rt for 15 min and then transferred via syringe to a solution
of the lactone 28 (46 mg, 0.121 mmol) in CH2Cl2 (2 mL). The
mixture was stirred at rt for 3 h, poured directly into 0.5 M HCl
(30 mL), and extracted with CH2Cl2 (3 × 15 mL), and then the
combined organics were dried (Na2SO4), filtered, and evaporated
in vacuo. The pure product was obtained by column chromatog-
raphy (1:2:2-1:1:0 Et2O/CH2Cl2/pentane as eluant), which gave
compound 29 (Rf ) 0.35, 1:1:1 pentane/CH2Cl2/Et2O) (30 mg,
0.0663 mmol, 55%) as a white solid: 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.10-7.35 (m, 10H), 5.75 (br s, 1H), 5.25 (d, J ) 9.2 Hz,
1H), 5.05 (AB system, J ) 13.6 Hz, 2H), 4.90 (s, 1H), 4.85 (s,
1
1H), 3.88 (br s, /2H), 3.79 (q, J ) 8.0 Hz, 1H), 3.66 (br s, 1H),
3.06-3.25 (m, 3H), 2.91 (d, J ) 7.6 Hz, 2H), 1.75-1.90 (m, 2H),
1.68 (s, 3H), 1.32-1.45 (m, 21/2H), 1.20-1.32 (m, 2H), 0.89 (t, J
) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 173.3, 156.6,
143.7, 138.3, 136.8, 129.3 (2C), 128.5 (2C), 128.4 (2C), 128.0,
127.8 (2C), 126.3, 114.0, 68.6, 66.5, 56.5, 50.9, 39.3, 38.9, 34.7,
31.4, 21.1, 20.0, 13.7; HRMS C27H36N2O4 [M + Na+] calcd
475.2573, found 475.2585.
(2R,4S,5S)-Isopropylhydroxyamino-6-phenylhexanoic Acid
N-Butylamide (30). The alkene 29 (15 mg, 0.0331 mmol) was
dissolved in MeOH (2 mL), and then PdCl2 (6 mg, 0.338 mmol)
was added. The mixture was stirred under an atmosphere of H2 for
18 h, and then the flask was flushed with N2 before the mixture
was filtered through Celite and the solids were washed with MeOH
(3 × 3 mL). The filtrates were evaporated to dryness in vacuo,
dissolved in CH2Cl2, poured into satd NaHCO3 (25 mL), and
extracted with CH2Cl2 (3 × 15 mL). The combined organics were
dried (Na2SO4), filtered, and evaporated in vacuo to give compound
30 (Rf ) 0.10-0.35, 20% MeOH in CH2Cl2) (10 mg, 0.0312 mmol,
94%) as a white solid: 1H NMR (400 MHz, CDCl3) δ (ppm) 7.05-
7.26 (m, 5H), 5.74 (br s, 1H), 3.09-3.30 (m, 3H), 2.86 (dd, J )
13.2, 4.0 Hz, 1H), 2.74 (dt, J ) 10.0, 4.4 Hz, 1H), 2.39 (dd, J )
13.2, 9.6 Hz, 1H), 2.05 (ddd, J ) 11.2, 8.4, 3.2 Hz, 1H), 1.72-
1.86 (m, 3H), 1.50 (ddd, J ) 13.6, 10.8, 2.8 Hz, 1H), 1.15-1.33
(m, 6H), 0.82-0.90 (m, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm)
175.3, 138.8, 129.3 (2C), 128.6 (2C), 126.4, 71.3, 57.2, 51.3, 40.8,
39.0, 35.2, 31.7, 30.5, 21.1, 20.4, 20.1, 13.7; HRMS C19H32N2O2
[M + Na+] calcd 321.2542, found 321.2544.
4-(2S-Iodomethyl-3-methylbutyl)-1-methoxy-2-(3-methoxy-
propoxy)benzene (35). Method 1. (2S)-2-[4-Methoxy-3-(3-meth-
oxypropoxy)benzyl]-3-methylbutan-1-ol44 (153 mg, 0.516 mmol)
was dissolved in CH2Cl2 (16 mL), and then PPh3 (444 mg, 1.168
mmol) and imidazole (112 mg, 1.168 mmol) were added. After 5
min, iodine (348 mg, 1.32 mmol) was added, and then the mixture
was stirred at rt for 16 h before it was poured into satd Na2S2O3
solution (30 mL) and extracted with CH2Cl2 (3 × 20 mL). The
combined organic portions were dried (MgSO4), filtered, and
evaporated in vacuo. The pure product was obtained by column
chromatography (5-20% EtOAc in pentane as eluant), which gave
iodide 35 (Rf ) 0.5, 10% EtOAc in pentane) (161 mg, 0.396 mmol,
77%) as a white solid. Method 2. Bromide 1344 (80 mg, 0.223
mmol) was dissolved in acetone, and then NaI (200 mg, 1.334
mmol) was added. The mixture was stirred at rt for 20 h, then
poured into water (30 mL) and extracted with CH2Cl2 (2 × 20
4774 J. Org. Chem., Vol. 71, No. 13, 2006

Synthesis of the Potent Renin Inhibitor Aliskiren
pentane) (294 mg, 0.506 mmol, 94%) as a colorless gum: 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.52 (d, J ) 5.6 Hz, 2H), 7.16-7.32
(m, 7H), 6.68 (d, J ) 8.0 Hz, 1H), 6.64 (d, J ) 2.0 Hz, 1H), 6.58
(dd, J ) 8.0, 2.0 Hz, 1H), 5.43 (d, J ) 8.8 Hz, 1H), 5.09 (AB
system, J ) 12.4 Hz, 2H), 4.35-4.43 (m, 1H), 4.00 (t, J ) 6.4 Hz,
2H), 3.74 (s, 3H), 3.47 (t, J ) 6.4 Hz,. 2H), 3.24 (s, 3H), 2.39-
2.50 (m, 2H), 1.99 (p, J ) 6.4 Hz, 2H), 1.50-1.74 (m, 4H), 0.81
(d, J ) 6.8 Hz, 3H), 0.76 (d, J ) 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 197,2, 155.8, 149.9 (2C), 148.3, 147.7,
138.3, 136.0, 133.0, 128.5 (2C), 128.2, 128.0 (2C), 128.0 (2C),
121.1, 114.3, 111.8, 69.3, 67.2, 65.9, 59.9, 58.5, 55.9, 42.0, 36.5,
33.0, 29.5, 28.6, 19.6, 17.5; HRMS C32H40N2O6S [M + Na+] calcd
603.2505, found 603.2520.
cooled to -78 °C before the addition of (S)-Alpine Hydride (1.1
mL, 0.55 mmol, 0.5 M in THF). The mixture was stirred at -78
°C for 24 h, satd NH4Cl solution (5 mL) was added carefully, and
the mixture was warmed to rt before being poured into water (40
mL) and extracted with EtOAc (3 × 20 mL). The combined
organics were dried (MgSO4), filtered, and evaporated in vacuo.
The pure product was obtained by column chromatography
(15-70% EtOAc in pentane as eluant), which gave compound 45
(Rf ) 0.25, 50% EtOAc) (124 mg, 0.235 mmol, 91%) as a 4:1
mixture of isomers as determined by 1H NMR. These were
separable by careful column chromatography (20-50% Et2O in
1:1 CH2Cl2/pentane as eluant), which gave isomerically pure 45
(Rf ) 0.45, 25% Et2O in CH2Cl2) (85 mg) and the corresponding
1
epimer (Rf ) 0.35, 25% Et2O in CH2Cl2) (21 mg). H NMR (400
γ-Ketoester 43. The thioester 42 (271 mg, 0.470 mmol) was
dissolved in anhydrous THF (7.5 mL) and the flask flushed with
argon for 10 min. Methyl acrylate (455 µL, 5.06 mmol) and tert-
butyl alcohol (112 µL, 1.52 mmol) were added, and then the mixture
cooled to -78 °C before a 0.1 M solution of SmI2 (20 mL, 2.00
mmol) was added via syringe. The mixture was stirred at -78 °C
for 2 d and then the flask flushed with O2 before satd NH4Cl (aq)
(5 mL) was added and the mixture warmed to rt. The mixture was
poured into 0.5 M HCl (30 mL) and extracted with EtOAc (3 ×
15 mL). The combined organics were washed with satd Na2S2O3
solution (20 mL), dried (MgSO4), filtered, and evaporated in vacuo.
The pure product was obtained by column chromatography
(20-50% EtOAc in pentane as eluant), which gave compound 43
(Rf ) 0.55, 50% EtOAc in pentane) (167 mg, 0.299 mmol, 64%)
as a clear oil: 1H NMR (400 MHz, CDCl3) δ (ppm) 7.26-7.36
(m, 5H), 6.80 (s, 1H), 6.76 (d, J ) 8.0 Hz, 1H), 6.69 (d, J ) 8.0
Hz, 1H), 5.30 (d, J ) 8.0 Hz, 1H), 5.09 (AB system, J ) 12.4 Hz,
2H), 4.33 (t, J ) 8.0 Hz, 1H), 4.09 (t, J ) 6.8 Hz, 2H), 3.81 (s,
3H), 3.64 (s, 3H), 3.55 (t, J ) 6.4 Hz), 3.31 (s, 3H), 2.79 (dt, J )
17.6, 7.6 Hz, 1H), 2.07 (p, J ) 6.4, 2H), 2.43-2.70 (m 5H), 1.44-
1.74 (m, 3H), 1.39 (t, J ) 11.2 Hz, 1H), 0.76-0.86 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 207.8, 172.7, 156.1, 148.3, 147.6,
136.3, 133.3, 128.4 (2C), 128.0, 127.8 (2C), 121.2, 114.3, 111.7,
69.3, 66.8, 65.9, 58.5, 58.1, 55.9, 51.7, 42.0, 37.0, 34.3, 32.1, 29.5,
28.3, 27.4, 20.1, 16.5; HRMS C31H43NO8 [M + Na+] calcd
580.2886, found 580.2867.
γ-Ketoester 44. The thioester 42 (275 mg, 0.473 mmol) was
dissolved in THF (7.5 mL), and then n-butyl acrylate (372 µL, 2.59
mmol) and tert-butyl alcohol (106 µL, 1.43 mmol) were added.
The mixture was cooled to -78 °C, and then SmI2 (0.1 M, 20 mL,
2.00 mmol) was added slowly via syringe. The mixture was stirred
at -78 °C for 3 d and then the flask flushed with O2 before satd
NH4Cl (aq) (5 mL) was added and the mixture warmed to rt. The
mixture was poured into 0.5 M HCl (40 mL) and extracted with
EtOAc (3 × 15 mL). The combined organics were washed with
satd Na2S2O3 solution (20 mL), dried (MgSO4), filtered, and
evaporated in vacuo. The pure product was obtained by column
chromatography (10-40% EtOAc in pentane as eluant), which gave
compound 44 (Rf ) 0.40, 30% EtOAc in pentane) (170 mg, 0.283
mmol, 60%) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.27-7.37 (m, 5H), 6.81 (d, J ) 1.6 Hz 1H), 6.77 (d, J )
8.0 Hz, 1H), 6.70 (dd, J ) 8.0, 1.6 Hz, 1H), 5.19 (1H, d, J ) 8.4
Hz, 1H), 5.03 (s, 2H), 4.28 (app br t, J ) 8.4 Hz, 1H), 3.94-4.06
(m, 4H), 3.75 (s, 3H), 3.49 (t, J ) 6.4 Hz, 2H), 3.25 (s, 3H), 2.68-
2.78 (m, 1H), 2.36-2.64 (m, 5H), 2.01 (p, 6.4 Hz, 2H), 1.48-
1.67 (m, 5H), 1.24-1-37 (m, 3H), 0.85 (t, J ) 7.2 Hz, 3H), 0.76
(d, J ) 7.2 Hz, 3H), 0.74 (d, J ) 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 207.9, 172.4, 156.2, 148.3, 147.7, 136.3,
133.4, 128.5 (2C), 128.1, 127.9 (2C), 121.2, 114.4, 111.7, 69.4,
66.8, 65.9, 64.6, 58.6, 58.1, 56.0, 42.0, 37.1, 34.4, 32.2, 30.5, 29.6,
28.3, 27.7, 20.2, 19.0, 16.9, 13.6; HRMS C34H49NO8 [M + Na+]
calcd 622.3356, found 622.3354.
MHz, CDCl3) δ (ppm) 7.26-7.36 (m, 5H), 6.72-6.77 (m, 2H),
6.64 (dd, J ) 8.4, 2.0 Hz, 1H), 5.13 (s, 2H), 4.82 (d, J ) 10.0 Hz,
1H), 4.42 (td, J ) 7.2, 1.6 Hz, 1H), 4.09 (t, J ) 6.4 Hz, 2H), 3.78-
3-88 (m, 1H), 3.82 (s, 3H), 3.55 (t, J ) 6.4 Hz, 2H), 3.31 (s, 3H),
2.60 (dd, J ) 13.6, 5.6 Hz, 1H), 2.36-2.48 (m, 3H), 2.12-2.23
(m, 1H), 2.07 (p, J ) 6.4 Hz, 2H), 1.95-2.05 (m, 1H), 1.61-1.73
(m, 2H), 1.49-1.58 (m, 1H), 1.30 (dd, J ) 13.6, 9.2, 3.2 Hz, 1H),
0.82 (d, J ) 6.8 Hz, 3H), 0.81 (d, J ) 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 176.9, 156.8, 148.2, 147.6, 136.3, 133.6,
128.5 (2C), 128.1, 127.8 (2C), 121.2, 114.4, 111.7, 82.6, 69.3, 66.8,
65.9, 58.5, 56.0, 51.9, 42.4, 37.1, 33.4, 29.6, 28.4, 27.9, 28.4, 27.9,
24.3, 20.2, 16.7; HRMS C30H41NO7 [M + Na+] calcd 550.2781,
found 550.2781.
Lactone 46. The lactone 45 (137 mg, 0.258 mmol) was dissolved
in THF (15 mL) and the mixture cooled to -78 °C. LiHMDS (0.70
mL, 0.70 mmol, 1 M in hexanes) was added and the mixture stirred
for 2 h before dropwise addition of acetone (0.70 mL, 9.54 mmol).
The mixture was stirred for an additional 2 h, and then satd
NH4Cl(aq) (5 mL) was added and the mixture allowed to warm to
rt. The mixture was poured into water (30 mL) and extracted with
EtOAc (3 × 20 mL), and then the combined organics were dried
(Na2SO4) filtered, and evaporated in vacuo. The pure product
was obtained by column chromatography (5:5:2-0:1:1 pentane/
CH2Cl2/Et2O as eluant), which gave compound 46 (Rf ) 0.30, 50%
Et2O in CH2Cl2) (133 mg, 0.234 mmol, 91%) an inseparable 5:1
mixture of isomers: 1H NMR (400 MHz, CDCl3) δ (ppm) 7.27-
7.37 (m, 5H), 6.71-6.78 (m, 2H), 6.64 (d, J ) 8.0 Hz, 1H), 5.13
(AB system, J ) 12.8 Hz, 2H), 4.70 (d, J ) 9.6 Hz, 1H), 4.42 (t,
J ) 6.0 Hz, 1H), 4.09 (t, J ) 6.4 Hz, 2H), 3.75-3.85 (m, 1H),
3.83 (s, 3H), 3.56 (t, J ) 6.4 Hz, 2H), 3.32 (s, 3H), 3.04 (brs, 1H),
2.51 (m, 4H), 2.44 (dd, J ) 12.8, 8.0 Hz, 1H), 2.03-2.25 (m, 2H),
1.46-1.63 (m, 3H), 1.31 (ddd, J ) 12.8, 9.2, 3.2 Hz, 1H), 1.25 (s,
3H), 1.20 (s, 3H), 0.83 (d, J ) 7.2 Hz, 3H), 0.81 (d, J ) 8.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 178.4, 156.8, 148.2,
147.6, 136.3, 133.5, 128.5 (2C), 128.2, 127.8 (2C), 121.2, 114.4,
111.8, 81.0, 71.4, 69.4, 66.9, 66.0, 58.5, 56.0, 52.8, 49.9, 42.4, 37.1,
33.1, 29.6, 28.2, 27.6, 27.5, 26.1, 20.2, 16.9; HRMS C33H47NO8
[M + Na+] calcd 608.3199, found 608.3201.
Lactone 47. Alcohol 51 (133 mg, 0.234 mmol) was dissolved
in CH2Cl2 (15 mL) and then the mixture cooled to 0 °C. PCl5 (210
mg, 1.01 mmol) dissolved in CH2Cl2 (5 mL) was added over 5
min via syringe then the mixture stirred for 2.5 h. Saturated
NaHCO3 solution (5 mL) was added, and then the mixture was
warmed to rt, poured into water (30 mL), and extracted with
CH2Cl2 (3 × 20 mL). The combined organic portions were dried
(MgSO4), filtered, and evaporated. The pure product was obtained
by column chromatography (20-50% EtOAc in pentane as eluant)
which gave compound 47 (Rf ) 0.60, 40% EtOAc in pentane) (132
mg, 0.233 mmol, 99%) as an inseparable 40:8:6 mixture of 47a,
47b, and 51: 1H NMR (400 MHz, CDCl3) δ (ppm) 7.28-7.37 (m,
5H), 6.72-6.77 (m, 2H), 6.64 (dd, J ) 8.4, 1.6 Hz, 1H), 5.14 (AB
system, J ) 12.0 Hz, 2H), 4.96 (s, 1H), 4.84 (s, 1H), 4.68 (d, J )
10.0 Hz, 1H), 4.45 (td, J ) 7.2, 1.6 Hz, 1H), 4.09 (t, J ) 6.8 Hz,
2H), 3.80-3.90 (m, 1H), 3.83 (s, 3H), 3.36 (t, J ) 6.4 Hz, 2H),
3.32 (s, 3H), 3.19 (dd, J ) 10.0, 5.2 Hz, 1H), 2.60 (dd, J ) 13.6,
Phenylmethyl [(1S,3S)-3-[[4-Methoxy-3-(3-methoxypropoxy)-
phenyl]methyl]-4-methyl-1-[(2S)-tetrahydro-5-oxo-2-furanyl]-
pentyl]carbamate (45). The γ-keto methyl ester 43 (144 mg, 0.257
mmol) was dissolved in THF (25 mL), and then the solution was
J. Org. Chem, Vol. 71, No. 13, 2006 4775

Lindsay and Skrydstrup
5.2 Hz, 1H), 2.40 (dd, J ) 13.6, 8.8 Hz, 1H), 2.12-2.30 (m, 2H),
2.09 (p, J ) 6.4 Hz, 2H), 1.79 (s, 3H), 1.60-1.72 (m, 3H), 1.47-
1.57 (, 1H), 1.31 (ddd, J ) 13.6, 8.8, 3.6 Hz, 1H), 0.82 (d, J ) 7.2
Hz, 3H), 0.81 (3H, d, J ) 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 176.6, 156.8, 148.1, 147.7, 140.1, 136.2, 133.6,
128.6 (2C), 128.2, 127.9 (2C), 121.2, 114.4, 113.9, 111.8, 81.2,
69.4, 67.0, 66.0, 58.6, 56.1, 52.1, 47.6, 42.5, 37.2, 33.5, 30.1, 29.6,
28.0, 20.7, 20.3, 16.8; HRMS C33H45NO7 [M + Na+] calcd
590.3094, found 590.3098.
(3S,5S)-Dihydro-5-[(1S,3S)-3-[[4-methoxy-3-(3-methoxypro-
poxy)phenyl]methyl]-4-methyl-1-amino-pentyl]-3-(1-methylethyl)-
2-(3H)-furanone (48). Alkene 47 (51 mg, 0.0898 mmol) was
dissolved in EtOH (5 mL), and then 10% Pd/C (10 mg) was added.
The mixture was stirred under an atmosphere of H2 for 2 d, and
then the flask was flushed with N2 before it was filtered through
Celite. The solids were washed with EtOH, and then the combined
filtrates were evaporated to dryness giving compound 48 (Rf ) 0.20,
5% MeOH in CH2Cl2) (39 mg, 0.0895 mmol 99%) as a 4:1 mixture
of diastereoisomers that was not purified any further: 1H NMR
(400 MHz, CDCl3) δ (ppm) 6.76 (d, J ) 8.0 Hz, 1H), 6.66-6.73
(m, 2H), 4.08 (t, J ) 6.4 Hz, 2H), 3.99 (dt, J ) 10.0, 6.4 Hz, 1H),
3.82 (s, 3H), 3.56 (t, J ) 6.0 Hz, 2H) 3.45 (s, 3H), 2.40-2.60 (m,
4H), 1.90-2.02 (m, 4H), 1.16-1.82 (m, 7H), 1.02 (d, J ) 6.4 Hz,
3H), 0.82-0.92 (m, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm)
178.0, 148.3, 147.7, 132.8, 121.4, 114.6, 111.9, 77.8, 69.4, 66.1,
58.5, 56.0, 53.4, 45.0, 40.6, 37.0, 30.6, 29.5, 29.2, 28.8, 26.5, 20.1,
19.5, 18.6, 17.5; HRMS C25H41NO5 [M + Na+] calcd 458.2882,
found 458.2896.
1,1-Dimethylethyl [(1S,3S)-3-[[4-Methoxy-3-(3-methoxypro-
poxy)phenyl]methyl]-4-methyl-1-[(2S,4S)-tetrahydro-4-(1-meth-
ylethyl)-5-oxo-2-furanyl]pentyl]carbamate (49).31 Amine 48 (39
mg, 0.0895 mmol) was dissolved in THF (1.0 mL), and then NEt3
(51 mg, 0.10 mmol) and di-tert-butyl dicarbonate (51 mg, 0.10
mmol) were added. The mixture was stirred at rt for 18 h, and
then all volatiles were removed in vacuo. The pure products were
obtained by careful column chromatography (5-40% EtOAc in
pentane as eluant), which gave isomerically pure 49 (Rf ) 0.60,
40% EtOAc in pentane) (30 mg, 0.0560 mmol, 63%) and a mixture
of 49 and 53 (Rf ) 0.55, 40% EtOAc in pentane) (10 mg, 0.0187
mmol, 21%). 49: 1H NMR (400 MHz, CDCl3) δ (ppm) 6.76 (d, J
) 8.0 Hz, 1H), 6.73 (s, 1H), 6.68 (d, J ) 8.0 Hz, 1H), 4.33-4.40
(m, 2H), 4.09 (t, J ) 6.4 Hz, 2H), 3.82 (s, 3H), 3.75-3.85 (m,
1H), 3.57 (t, J ) 6.4 Hz, 2H), 3.35 (s, 3H), 2.62 (dd, J ) 13.6, 5.6
Hz, 1H), 2.54 (td, J ) 10.0, 6.0 Hz,), 2.38 (dd, J ) 14.0, 9.6 Hz,
1H), 2.00-2.20 (m, 5H), 1.33-1.70 (m, 3H), 1.45 (s, 9H), 1.22-
1.32 (m, 1H), 1.00 (d, J ) 6.8 Hz, 3H), 0.93 (d, J ) 6.4 Hz, 3H),
0.82 (d, J ) 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm)
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
(3C), 27.9, 26.8, 20.6, 20.5, 18.6, 16.7; HRMS C30H49NO7 [M +
Na+] calcd 558.3407, found 558.3406.
(2R,4S,5S,7S)-Isopropylhydroxy(N-butoxycarbamoyl)ami-
noisopropyl-8-(4-methoxy-3-(3-methoxypropoxy)benzenoctano-
ic Acid n-Butylamide (50).49,50 n-Butylamine (120 mg, 1.641
mmol) was dissolved in CH2Cl2 (2 mL), and then trimethylalumi-
num (0.8 mL, 2 M solution in toluene, 1.60 mmol) was added.
The mixture was stirred at rt for 30 min and then transferred
via syringe to a solution of lactone 49 (14 mg, 0.0261 mmol) in
CH2Cl2 (1 mL). The mixture was stirred at rt for 20 h, and then
the reaction was quenched by careful addition of satd NH4Cl
solution (3 mL). The mixture was poured into 1 M NaHCO3 solu-
tion (20 mL) and extracted with CH2Cl2 (4 × 15 mL). The com-
bined organic portions were dried (MgSO4), filtered, and evaporated.
The pure product was obtained by column chromatography
(15-60% EtOAc in pentane as eluant) which gave compound 50
(Rf ) 0.30, 50% EtOAc in pentane) (9 mg, 0.0152 mmol, 58%) as
a colorless solid: 1H NMR (400 MHz, CDCl3) δ (ppm) 6.72-
6.82 (m, 2H), 6.69 (d, J ) 8.0 Hz, 1H), 5.70 (br s, 1H), 4.67 (d, J
) 8.8 Hz, 1H), 4.10 (t, J ) 5.6 Hz, 2H), 3.82 (s, 3H), 3.74 (br s,
1H), 3.57 (t, J ) 6.4 Hz, 2H), 3.48-3.55 (m, 1H), 3.38-3.46 (m,
1H), 3.35 (s, 3H), 3.27-3.37 (m, 1H), 3.12-3.23 (m, 1H), 2.61
(dd, J ) 13.2, 4.4 Hz, 1H), 2.38 (dd, J ) 14.0, 8.8 Hz, 1H), 2.08
(p, J ) 6.4 Hz, 2H), 1.98 (td, J ) 8.8, 3.2 Hz, 1H), 1.80-1.94 (m,
4H), 1.44 (s, 9H), 1.16-1.80 (m, 7H), 0.89-0.95 (m, 9H), 0.82
(d, J ) 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 176.2,
156.9, 148.4, 147.7, 134.5, 121.5, 114.7, 111.8, 79.3, 71.3, 69.6,
66.2, 58.8, 56.2, 54.1, 51.7, 42.4, 39.3, 37.6, 34.7, 32.8, 31.8, 29.8,
29.8, 28.6 (3C), 28.3, 21.4, 2p0.6, 20.5, 20.3, 17.0, 13.9; HRMS
C34H60N2O7 [M + Na+] calcd 631.4298, found 631.4294.
Lactone 51. Lactone 47 (36 mg, 0.0634 mmol) was dissolved
in CH3CN (1.0 mL), and then NEt3 (0.5 mL) and 2-hydroxypyridine
(10 mg, 0.104 mmol) were added. The mixture was heated at 80
°C for 2 d, and then all volatiles were removed in vacuo. The pure
product was obtained by column chromatography (15-50% EtOAc
in pentane as eluant) which gave compound 51 (Rf ) 0.55, 1:1:1
pentane/CH2Cl2/Et2O) (32 mg, 0.0564 mmol, 89%) as a white
solid: 1H NMR (400 MHz, CDCl3) δ (ppm) 7.27-7.36 (m, 5H),
6.73-6.78 (m 2H), 6.65 (dd, J ) 8.0, 1.2 Hz, 1H), 5.11 (AB system,
J ) 12.4 Hz, 2H), 4.68 (d, J ) 12.4 Hz, 1H), 4.37 (t, J ) 6.8 Hz,
1H), 4.09 (t, J ) 6.4 Hz, 2H), 3.80-3.90 (m, 1H), 3.83 (s, 3H),
3.56 (t, J ) 6.4 Hz, 2H), 3.32 (s, 3H), 2.82 (dd, J ) 16.4, 8.0 Hz,
1H), 2.58-2.68 (m, 2H), 2.41 (dd, J ) 13.6, 9.2 Hz, 1H), 2.20 (s,
3H), 2.08 (p, J ) 6.4, 2H), 1.77 (s, 3H), 1.63-1.74 (m, 2H), 1.48-
1-58 (m, 1H), 1.30 (ddd, J ) 14.0, 9.6, 3.2 Hz, 1H), 0.83 (d, J )
6.4 Hz, 3H), 0.81 (d, J ) 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 170.1, 157.0, 150.6, 148.4, 147.7, 136.6, 133.9, 128.6 (2C),
128.2, 127.9 (2C), 121.4, 119.0, 114.6, 111.9, 78.2, 69.9, 66.1, 58.8,
56.2, 52.6, 42.6, 37.3, 33.4, 31.0, 29.8, 28.0, 24.6, 20.5, 20.0, 16.8;
HRMS C33H45NO7 [M + Na+] calcd 590.3094, found 590.3097.
(3S,5S)-Dihydro-5-[(1S,3S)-3-[[4-methoxy-3-(3-methoxypro-
poxy)phenyl]methyl]-4-methyl-1-[(phenylmethyl)amino]pentyl]-
3-(1-methylethyl)-2(3H)-furanone (52).30 Amine 48 (29 mg,
0.0669 mmol) was dissolved in ethanol (1.0 mL) and then the
solution cooled to 0 °C before benzaldehyde (20 µL, 0.197 mmol)
was added. The mixture was stirred at 0 °C for 90 min. NaBH4
(10 mg, 0.264 mmol) was then added quickly and stirring continued
at rt for a further 40 min. The mixture was poured into water (20
mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic
portions were dried (MgSO4), filtered, and evaporated. The pure
product was obtained by column chromatography (5:5:1-0:1:1
pentane/CH2Cl2/Et2O as eluant), which gave 52 (Rf ) 0.45, 1:1:1
pentane/CH2Cl2/Et2O) (24 mg, 0.0457 mmol, 68%) and the dia-
stereoisomer (Rf 0.25, 1:1:1 pentane/CH2Cl2/Et2O) (6 mg, 0.0114
mmol, 17%) as colorless oils. 52: 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.14-7.27 (m, 5H), 6.70 (d, J ) 8.4 Hz 1H), 6.62 (d, J )
2.0 Hz, 1H), 6.56 (dd, J ) 8.4, 2.0 Hz, 1H), 4.23 (ddd, J ) 8.0,
6.0, 4.8 Hz, 1H), 4.00 (t, J ) 6.4 Hz, 2H), 3.77 (d, J ) 12.8 Hz,
1H), 3.76 (s, 3H), 3.67 (d, J ) 12.8 Hz, 1H), 3.49 (t, J ) 6.0 Hz,
2H), 3.27 (s, 3H), 2.38-2.47 (m, 3H), 2.33 (dd, J ) 13.6, 6.8 Hz,
1H), 1.98-2.10 (m, 3H), 1.77-1.89 (m, 2H), 1.58-1-69 (m, 2H),
1.30-1.40 (br s, 1H), 1.43 (ddd, J ) 14.0, 7.6, 4.8 Hz, 1H), 1.22
(ddd, J ) 14.0, 7.2, 5.6 Hz, 1H), 0.91 (d, J ) 6.8 Hz, 3H), 0.79-
0.84 (m, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 179.4, 148.4,
147.9, 140.7, 134.0, 128.5 (2C), 128.3 (2C), 127.1, 121.3, 114.3,
111.8, 80.9, 69.5, 66.2, 58.8, 58.8, 56.1, 51.9, 46.0, 42.5, 37.3, 31.7,
29.7, 29.1, 26.6, 20.5, 19.2, 18.4, 18.3; HRMS C32H47NO5 [M +
Na+] calcd 548.3351, found 548.3373.
(3S,5S)-Dihydro-5-[(1R,3S)-3-[[4-methoxy-3-(3-methoxypro-
poxy)phenyl]methyl]-4-methyl-1-aminopentyl]-3-(1-methylethyl)-
2-(3H)-furanone (53). Alkene 51 (32 mg, 0.0564 mmol) was
dissolved in EtOH (5 mL), and then 10% Pd/C (15 mg) was added.
The mixture was stirred under an atmosphere of H2 for 18 h, and
(49) John, V.; Maillard, M. PCT Int. Appl. (Elan Pharmaceuticals, Inc.)
Wo, 2003, 363 pp.
(50) Goeschke, R.; Maibaum, J. K.; Schilling, W.; Stutz, S.; Rigollier,
P.; Yamaguchi, Y.; Cohen, N. C.; Herold, P. Eur. Pat. Appl. (Ciba-Geigy
A.-G., Switzerland) Ep, 1995, 115 pp.
4776 J. Org. Chem., Vol. 71, No. 13, 2006

Synthesis of the Potent Renin Inhibitor Aliskiren
then the flask was flushed with N2 before it was filtered through
Celite. The solids were washed with EtOH and then the combined
filtrates evaporated to dryness giving compound 53 (23 mg, 0.0528
mmol, 94%) as a 10:1 mixture of diastereoisomers: 1H NMR (400
MHz, CDCl3) δ (ppm) 6.76 (d, J ) 8.0 Hz, 1H), 6.66-6.74 (m,
2H), 4.08 (t, J ) 6.4 Hz, 2H), 3.99 (dt, J ) 10.0, 6.4 Hz, 1H), 3.82
(s, 3H), 3.56 (t, J ) 6.0 Hz, 2H), 3.45 (s, 3H), 2.40-2.60 (m, 4H),
2.00-2.02 (m, 4H), 1.16-1.82 (m 7H), 1.02 (d, J ) 6.4 Hz, 3H),
0.82-0.92 (m, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 177.7,
148.3, 147.7, 133.9, 121.1, 114.3, 111.7, 82.9, 69.3, 66.1, 58.6,
56.0, 53.6, 46.9, 41.9, 37.7, 34.0, 29.8, 29.6, 27.5, 27.0, 20.6, 19.9,
18.2, 17.5; HRMS C25H41NO5 [M + Na+] calcd 458.2882, found
458.2896.
1,1-Dimethylethyl [(1S,3S)-3-[[4-Methoxy-3-(3-methoxypropoxy)-
phenyl]methyl]-4-methyl-1-[(2S,4R)-tetrahydro-4-(1-
methylethyl)-5-oxo-2-furanyl]pentyl]carbamate (54). Amine 53
(16 mg, 0.0369 mmol) was dissolved in THF (0.4 mL), and then
NEt3 (21 mg, 0.10 mmol) and di-tert-butyl dicarbonate (21 mg,
0.10 mmol) were added. The mixture was stirred at rt for 18 h,
and then all volatiles were removed in vacuo. The pure product
was obtained by column chromatography (10-40% EtOAc in
pentane as eluant) which gave compound 54 (Rf ) 0.60, 40%
EtOAc in pentane) (16 mg, 0.0299 mmol, 81%) as a gum: 1H NMR
(400 MHz, CDCl3) δ (ppm) 6.72-6.78 (m, 2H), 6.69 (dd, J ) 8.4,
2.0 Hz, 1H), 4.47 (d, J ) 10.4 Hz, 1H), 4.30 (dd, J ) 9.6, 6.4 Hz,
1H), 4.09 (t, J ) 6.4 Hz, 2H), 3.76-3.85 (m, 1H), 3.82 (s, 3H),
3.57 (t, J ) 6.4 Hz, 2H), 3.34 (s, 3H), 2.64 (dd, J ) 14.0, 5.6 Hz,
1H), 2.58 (ddd, J ) 12.4, 9.2, 4.8 Hz, 1H), 2.38 (dd, J ) 14.0, 9.6
Hz, 1H), 2.03-2.26 (m, 4H), 1.84 (td, J ) 12.0, 10.8 Hz, 1H),
1.50-1.72 (m, 3H), 1.44 (s, 9H), 1.27 (ddd, J ) 14.4, 9.6, 3.6 Hz,
1H), 1.01 (d, J ) 6.4 Hz, 3H), 0.90 (d, J ) 6.8 Hz, 3H), 0.82 (d,
J ) 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 178.0,
156.2, 148.3, 147.7, 133.8, 121.4, 114.5, 80.4, 79.5, 69.5, 66.0,
58.6, 56.1, 50.5, 46.3, 42.4, 37.1, 33.6, 29.6, 28.3 (3C), 27.7, 27.5,
26.1, 20.5, 20.4, 17.9, 16.6; HRMS C30H49NO7 [M + Na+] calcd
558.3407, found 558.3406.
mmol) was dissolved in CH2Cl2 (2 mL) and then trimethylaluminum
(0.8 mL, 2 M solution in toluene, 1.60 mmol) was added. The
mixture was stirred at rt for 30 min and then transferred via syringe
to a solution of lactone 47 (15 mg, 0.0280 mmol) in CH2Cl2 (1
mL). The mixture was stirred at rt for 2 d and then the reaction
quenched by careful addition of satd NH4Cl solution (3 mL). The
mixture was poured into 1 M NaHCO3 solution (20 mL) and
extracted with CH2Cl2 (4 × 15 mL). The combined organic portions
were dried (MgSO4), filtered, and evaporated. The pure product
was obtained by column chromatography (1-5% MeOH in
CH2Cl2 as eluant) which gave compound 55 (Rf ) 0.33, 5% MeOH
in CH2Cl2) (8 mg, 0.0135 mmol, 48%) as a colorless solid: 1H
NMR (400 MHz, CDCl3) δ (ppm) 6.72-6.80 (m, 2H), 6.71 (d, J
) 8.0 Hz, 1H), 5.77 (t, J ) 5.6 Hz, 1H), 4.76 (d, J ) 10.0 Hz,
1H), 4.05-4.15 (m, 2H), 3.82 (s, 3H), 3.58-3.67 (m, 1H), 3.57 (t,
J ) 6.4 Hz, 2H), 3.45-3.52 (m, 1H), 3.45 (s, 3H), 3.24-3.34 (m,
1H), 3.10-3.24 (m, 1H), 2.61 (dd, J ) 13.2, 6.4 Hz, 1H), 2.53 (d,
J ) 4.0 Hz, 1H), 2.38 (dd, J ) 14.0, 9.2 Hz, 1H), 2.08 (p, J ) 6.4
Hz, 2H), 1.73-1.94 (m, 4H), 1.40-1-70 (m, 5H), 1.45 (s, 9H),
1.25-1.40 (m, 2H), 1.14 (ddd, J ) 13.6, 8.8, 4.8 Hz, 1H), 0.87-
0-94 (m, 9H), 0.83 (d, J ) 2.8 Hz, 3H), 0.82 (d, J ) 2.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ (ppm) 175.6, 156.6, 148.4, 147.7,
134.5, 121.6, 114.8, 111.9, 79.1, 73.0, 69.6, 66.2, 58.8, 56.2, 51.6,
51.4, 42.2, 39.4, 37.3, 34.4, 33.2, 31.9, 31.6, 29.8, 28.6 (3C), 28.1,
20.9, 20.3, 20.3, 20.2, 17.2, 13.9; HRMS C34H60N2O7 [M + Na+]
calcd 631.4298, found 631.4089.
Acknowledgment. We are deeply appreciative of generous
financial support from the Danish National Research Foundation,
the Lundbeck Foundation, and the University of Aarhus.
1
Supporting Information Available: Copies of H NMR and
13C NMR spectra for all new compounds and experimental pro-
tocols for preparation of compounds 25a,b,e,f and 26b-f. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(2S,4S,5S,7S)-Isopropylhydroxy-(N-butoxycarbamoyl)ami-
noisopropyl-8-(4-methoxy-3-(3-methoxypropoxy)benzenoctano-
ic Acid n-Butylamide (55).49,50 n-Butylamine (120 mg, 1.641
JO060296C
J. Org. Chem, Vol. 71, No. 13, 2006 4777