A convergent synthesis of the renin inhibitor SPP-100 using a nitrone intermediate

Article abstract of DOI:10.1016/S0040-4039(01)00883-8

The total synthesis of SPP-100 and its C-5 epimer involves the construction of the β-amino alcohol segment via addition of the Grignard reagent derived from 3-aryl-2-isopropyl-1-chloropropane to the nitrone functional group installed at C-4 of the pseudoe

Full text of DOI:10.1016/S0040-4039(01)00883-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4819–4823
A convergent synthesis of the renin inhibitor SPP-100 using a
nitrone intermediate
Alessandro Dondoni,* Geert De Lathauwer and Daniela Perrone
Dipartimento di Chimica, Laboratorio di Chimica Organica, Universita` di Ferrara, Via L. Borsari 46, I-44100 Ferrara, Italy
Received 4 May 2001; accepted 22 May 2001
Abstract—The total synthesis of SPP-100 and its C-5 epimer involves the construction of the b-amino alcohol segment via
addition of the Grignard reagent derived from 3-aryl-2-isopropyl-1-chloropropane to the nitrone functional group installed at C-4
of the pseudoephedrine spiroanellated g-butyrolactone derivative. © 2001 Elsevier Science Ltd. All rights reserved.
The hydroxyethylene dipeptide isostere 1 represents a
novel class of dipeptide transition state mimetics exert-
ing a pronounced and long-lasting blood-pressure
precursor of S-2 was the corresponding azido deriva-
tive. Hence, the amino group in S-2 was introduced by
coupling the cerium reagent derived from 3-aryl-2-iso-
propyl-1-chloropropane 3 and the (1S,2S)-(+)-pseu-
doephedrine spiroanellated g-lactone-aldehyde 4,
followed by the removal of the pseudoephedrine
residue, substitution of the hydroxyl by the azido group
via brosylation and reaction with NaN3, and reduction
of N3 to NH2. The pseudoephedrine residue played a
double role in this synthesis as it served as a chiral
auxiliary in the asymmetric synthesis of 4 starting from
reduction in laboratory animals.1 Compound
1
employed as the hemi-fumarate2 proved to be a highly
potent human renin inhibitor and therefore, was
selected for clinical investigation. The synthesis of 1 has
been very recently reported by research groups at
Novartis by two convergent methods,3,4 the more
efficient one4 involving the functionalized chiral amino
lactone S-2 as a key intermediate (Scheme 1). The
O
O
Me
HO
Me
Me
Me
O
H
N
NH2
H2N
Me
H2N
S
5
6
Me
MeO
O
O
Ar
Me
Me
MeO
Me
Me
1
S-2
Ph
Me
MeO
O
O
N
Me
Me
Me
Cl
Me
O
MeO
Me
X
3
4, X = O
5, X = N+(O )Bn
-
Scheme 1. Retrosynthetic analysis of SPP-100, 1.
Keywords: nitrones; amination; renin inhibitor; dipeptide isostere.
* Corresponding author. E-mail: adn@dns.unife.it
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00883-8

4820
A. Dondoni et al. / Tetrahedron Letters 42 (2001) 4819–4823
isovaleryl chloride5 via the Myers amide-based asym-
metric alkylation methodology6 and as a protective
group of the lactone carbonyl in the organometallic
addition to the formyl group. This key step afforded a
mixture of diastereomeric R- and S-alcohols in 85:15
ratio and 51% overall yield. A higher selectivity (96:4)
but a substantially lower yield (33%) was registered by
carrying the reaction in the presence of N,N,N%,N%-tet-
ramethylethylenediamine (TMEDA). The instability of
the aldehyde 4 constitutes an additional drawback in
this synthesis.7 Hence, we would like to report here a
new convergent synthesis of the amino lactone S-2 and
its epimer R-2 using the stable and crystalline N-benzyl
nitrone 5 derived from the aldehyde 4. We sought this
method as a more straightforward entry to the b-amino
alcohol moiety of 1, avoiding the three-step reaction
sequence through the azide intermediate. This new syn-
thetic route evolved from our recent work on the use of
chiral aldonitrones in synthetic approaches to aminated
systems.8,9 The convenient introduction of the amino
functionality via addition of nucleophiles to nitrones
relies in general on the superior properties of nitrones,
such as their ease of preparation, stability, and high
reactivity, over other imino compounds. This method-
ology appears to be highlighted below as well as in the
synthetic approach to SPP-100, the hemifumarate (SPP-
100B) of which is a potential drug against a disease of
great human relevance.2
Starting from the readily available and enantiomerically
pure (1S,2S)-(+)-pseudoephedrine protected lactone-
alcohol 6 (three steps from (+)-pseudoephedrine iso-
valeramide, 40% yield),4 the nitrone 5 was prepared
through the aldehyde 4 in 88% isolated yield (Scheme
2). Crude 4 was transformed into 5 via the standard
nitrone synthesis8 involving condensation with N-ben-
zylhydroxylamine in the presence of anhydrous sodium
sulfate. This nitrone was easily purified by crystalliza-
tion and stored for several days at room temperature
without appreciable decomposition.10 The assigned Z-
Ph
Me
Ph
Me
Ph
Me
O
N
Me
O
N
Me
Me
Me
O
N
Me
Me
Me
Me
Me
a
b
O
O
O
88%
O
+
N
O
OH
Bn
4
5
6
Scheme 2. Reagents and conditions: (a) SO3·pyridine, Et3N, DMSO/CH2Cl2 (2:1), 0°C to rt, 1 h; (b) PhCH2NHOH, Na2SO4
(anhydrous), CH2Cl2, rt, 2 h.
Me
Ph
Me
Ph
Me
N
O
Me
N
O
Me
Me
Me
Me
a, b
Ar
Cl
Me
O
HO
N
O
HO
N
+
Ph
Ar
Ph
Ar
Me
R
S
3
Me
Me
Me
Me
S-7
MeO(CH2)3O
MeO
R-7
= Ar
Scheme 3. Reagents and conditions: (a) Mg, 1,2-dibromoethane, THF, 45°C, 1 h; (b) nitrone 5, THF (see Table 1).
Table 1. Addition of the grignard reagent derived from 3 to the nitrone 5 in THF
Run Additive
Temp. (°C)
Time (h)
Grignard reagent (2 equiv.)
Ratioa R-7:S-7
Overall yieldb R-7+S-7 (%)
1
2
3
4
5
–
–
–
−10
−40
−10
−10
−10
15
15
6
15
15
–
–
70:30
85:15
80:20
65:35
45:55
77
62
51
32
47
c
+CeCl3
–
–
TMEDA
DMPU
a Determined by NMR analysis of the isolated mixture of products.
b Isolated products by chromatography.
c Prepared by addition of 4 equiv. of CeCl3 to the preformed Grignard reagent.

A. Dondoni et al. / Tetrahedron Letters 42 (2001) 4819–4823
4821
configuration based on the nuclear Overhauser effect
between CHꢀN and CH2Ph signals,8a was confirmed by
X-ray crystallography.11
created stereocenter of compounds R-7 and S-7 was
established following their transformation into the
target product 1 and its C-5 epimer.
The key step in the new convergent approach to 1 was
carried out by coupling nitrone 5 and the Grignard
The stereomers R-7 and S-7 obtained as in run 1 were
separated by medium-pressure column chromatography
(6 bar, silica, cyclohexane–acetone 9:1, plus 0.5% Et3N)
and the major product R-7 was subjected to suitable
elaborations.14 Guided by our earlier work on the
deoxygenation of nitrone–organometal adducts,8c,15 R-
7 was treated with Zn/Cu(OAc)2 in AcOH–H2O
(Scheme 4). In addition to the desired transformation
of the N(OH)Bn to the NHBn group induced by the
zinc–copper couple, the mild acid conditions caused the
cleavage of the amide spiroacetal, giving rise to the
formation of the N-benzylamino lactone R-2 in a single
step. Hence, the implementation of the direct introduc-
tion of the amino group via nitrone chemistry appeared
to have been demonstrated. Next, opening of the lac-
tone ring by 3-amino-2,2-dimethylpropionamide
(ADPA) afforded compound 8, thus, completing the
construction of the hydroxyethylene dipeptide isostere
skeleton. This compound was debenzylated by
hydrogenolysis over Pd/C to give the amino-free
product 9, the C-5 epimer of 1. The product 9 was
reagent prepared from the chiral alkyl chloride12
3
(Scheme 3). As opposed to the unsuccessful addition4 of
organometallic reagents to imines derived from the
aldehyde 4, the Grignard reagent prepared from 3
reacted readily with 5 between −10 and −40°C to give
mixtures of N-alkyl,N-benzylhydroxylamines R-7 and
S-7 in satisfactory overall yields and diastereoselectivity
in favor of the former isomer (Table 1, runs 1 and 2).
The use of the cerium reagent obtained from the Grig-
nard reagent by transmetallation with cerium chloride
gave a similar mixture of products but in lower yield
(run 3). Also the use of TMEDA as an additive con-
curred to reduce the overall yield of isolated products
(run 4). A tendency toward inversion of diastereoselec-
tivity was observed by the use of the chelate complex-
destroying agent 1,3-dimethyl-3,4,5-tetrahydro-2(1H)-
pyrimidinone (DMPU) (run 5). However, a substantial
predominance of the desired S-epimer could not be
achieved.13 The absolute configuration at the newly
O
Me
O
Me
O
Me
HO
H
N
Me
Me
Me
O
H
N
Ph
Ar
H
N
NH2
Ph
Ar
R
b
a
R-7
53%
41%
Me
Me
Me
Me
8
N-Bn R-2
Me
RO
Me
Me
Me
H
N
RHN
NH2
c
O
O
MeO(CH2)3O
MeO
87%
Me
Me
9, R = H
d
9a, R = Ac
Scheme 4. Reagents and conditions: (a) Zn/Cu(OAc)2, AcOH–H2O; rt, 55 h; (b) ADPA, 2-OH-pyridine, Et3N, 80°C, 72 h; (c) H2,
Pd/C, MeOH, rt, 3 h; (d) Ac2O, pyridine, rt 5 h.
Me
AcO
Me
Me
Me
O
H
N
NH2
AcHN
O
MeO(CH2)3O
MeO
a,b,c,d
R-7 + S-7
9a
+
Me
Me
1a
Scheme 5. Reagents and conditions: a, b, c and d, see Scheme 4.

4822
A. Dondoni et al. / Tetrahedron Letters 42 (2001) 4819–4823
isolated and characterized as the bis-acetyl derivative
9a.
L.; Merino, P.; Tejero, T.; Bertolasi, V. Chem. Eur. J.
1995, 1, 505; (b) Dondoni, A.; Perrone, D. Aldrichimica
Acta 1997, 30, 35; (c) Dondoni, A. Synthesis 1998, 1691;
(d) Dondoni, A.; Perrone, D.; Rinaldi, M. J. Org. Chem.
1998, 63, 9252; (e) Dondoni, A.; Perrone, D. Tetrahedron
Lett. 1999, 40, 9375; (f) De Risi, C.; Dondoni, A.;
Perrone, D.; Pollini, G. P. Tetrahedron Lett. 2001, 42,
3033.
The same reaction sequence described above was
repeated starting from a mixture of the adducts R-7
and S-7 (70:30). Each reaction (Scheme 5) was carried
out using the crude reaction mixture obtained in the
previous step. The major final isolated product was 9a
while the minor product was identical to compound 1a,
obtained by acetylation of an authentic sample of 1.
9. For a recent and comprehensive review on nucleophilic
additions to nitrones, see: Lombardo, M.; Trombini, C.
Synthesis 2000, 759.
10. Compound 5: mp 123–124°C (from cyclohexane); [h]D=
+27 (c 0.8, CHCl3). 1H NMR (selected, 300 MHz,
CDCl3): l 7.47–7.30 (10H, m), 6.86 (1H, d, J=4.8 Hz),
5.24 (1H, m), 4.92 (2H, s), 4.49 (1H, d, J=8.6 Hz), 2.85
(1H, dq, J=6.4, 8.6 Hz), 2.35 (1H, ddd, J=9.6, 12.2, 12.4
Hz), 2.28 (3H, s), 2.17 (1H, ddd, 3.8, 8.4, 12.2 Hz), 1.86
(1H, dqq, J=3.8, 6.0, 6.2 Hz), 1.73 (1H, dt, J=8.4, 12.4
Hz), 1.13 (3H, d, J=6.0 Hz), 1.05 (3H, d, J=6.2 Hz),
0.92 (3H, d, J=6.4 Hz).
11. Private communication from Professor V. Bertolasi (Cen-
tro di Strutturistica Diffrattometrica, Dipartimento di
Chimica, Universita` di Ferrara, I-44100 Ferrara, Italy,
e-mail: m38@unife.it) to whom enquiries regarding the
X-ray crystal structure analysis should be addressed.
12. Also the preparation of this building block was centered
In conclusion, a new synthetic approach to 1, the
substrate for the preparation of the antihypertensive
drug SPP-100B, and its C-5 epimer 9 has been dis-
closed. The use of the stable and crystalline nitrone 5 as
a key intermediate permits a rapid entry to the b-amino
alcohol moiety, thus reducing the number of steps and
the troublesome manipulation of an unstable com-
pound such as the g-lactone-aldehyde 4. Hence, this
new and operatively simple synthetic route appears to
be quite attractive, particularly in a large-scale synthe-
sis. However, the search for conditions giving a more
favorable stereoselectivity of the key coupling reaction
toward the desired product S-7 is a crucial issue which
is actively addressed in our laboratory.
on the Myers asymmetric alkylation of
a pseu-
doephedrine derived amide followed by removal of the
chiral auxiliary (see Ref. 4). A stock solution of the
Grignard reagent for various experiments (Table 1) was
prepared by slow addition of 3 (mp 56–57°C (MeOH);
[h]D=+48 (c 1.0, CHCl3)) and catalytic 1,2-dibro-
moethane in THF to a suspension of Mg powder (dried
by heating for 8 h at 120°C under moderate vacuum (1
mmHg)) in THF at 40–45°C containing a few crystals of
I2. The mixture was heated at the same temperature for
one additional hour. Afterward, a sample was quenched
with water and analyzed by 1H NMR spectroscopy.
Mixtures containing a substantial amount (more than
10%) of the Wurtz-type side-product were discarded.
13. Given the complexity of the chiral moiety of the nitrone
5, the stereochemical outcome of the organometallic
addition is open to various conjectures. Tunable syn/anti
selectivity was reported in addition reactions of
organometallic reagents to chiral a-alkoxy nitrones by
complexation with Lewis acids. Stereochemical models
such as Felkin–Anh–Houk, and similar ones, appeared to
give a satisfactory explanation for reactions of rather
simple compounds while exceptions were reported in the
case of nitrones bearing complex chiral substituents (see
Ref. 8a).
Acknowledgements
We thank Professor Daniel Bellus (Ciba Specialty
Chemicals, Basel, Switzerland) for bringing this pro-
gram to our attention and for fruitful discussions after-
wards. The entire project including a post-doctoral
fellowship to G.D.L. was financially supported by
Speedel Pharma AG, Basel, Switzerland.
References
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Yamaguchi, Y.; Schilling, W.; Wood, J. M. XVth EFMC
International Symposium on Medicinal Chemistry, Edin-
burgh (UK), 6–10 September 1998, Abstract Book p. 230.
2. The hemifumarate of 1 was originally assigned the iden-
tification number CGP60536B by Novartis (see Refs. 3
and 4). This compound has been renamed as SPP-100B
(generic name: Aliskiren) by Speedel Pharma AG, a
licensee of Novartis.
3. Ru¨eger, H.; Stutz, S.; Go¨schke, R.; Spindler, F.;
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14. Unlike R-7, the epimer S-7 could not be isolated in a
pure form. Compound R-7: oil, [h]D=+54 (c 1.0,
1
CHCl3). H NMR (300 MHz, CDCl3): l 7.48–7.23 (10H,
5. Dragovich, P. S.; Prins, T. J.; Zhou, R. J. Org. Chem.
m), 6.77–6.75 (3H, m), 4.99 (1H, bs), 4.59 (1H, dt, J=4.1,
6.8 Hz), 4.50 (1H, d, J=8.8 Hz), 4.08 (1H, dt, J=6.4, 9.5
Hz), 4.00 (1H, dt, J=6.6, 9.5 Hz), 3.82 (3H, s), 3.80 (1H,
d, J=13.7 Hz), 3.72 (1H, d, J=13.7 Hz), 3.54 (2H, t,
J=6.2 Hz), 3.33 (3H, s), 2.94 (1H, dt, J=4.1, 8.0 Hz),
2.86 (1H, dq, J=6.1, 8.8 Hz), 2.70 (1H, dd, J=5.4, 13.7
Hz), 2.34 (1H, dd, J=9.0, 13.7 Hz), 2.26 (3H, s), 2.07
(2H, ddt, J=6.2, 6.4, 6.6 Hz), 2.05–1.43 (8H, m), 1.12
(3H, d, J=5.8 Hz), 1.08 (3H, d, J=5.1 Hz), 1.06 (3H, d,
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which decomposed substantially under chromatographic
purification.
8. (a) Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F.

A. Dondoni et al. / Tetrahedron Letters 42 (2001) 4819–4823
4823
Hz). Compound S-7: 1H NMR (300 MHz, CDCl3): l
7.52–7.26 (10H, m), 6.86–6.72 (3H, m), 5.58 (1H, bs),
4.54 (1H, d, J=8.4 Hz), 4.48 (1H, m), 4.28 (1H, d,
J=12.9 Hz), 4.09 (1H, t, J=6.3 Hz), 3.99 (1H, d, J=12.9
Hz), 3.86 (3H, s), 3.56 (2H, t, J=6.3 Hz), 3.36 (3H, s),
3.02–2.88 (2H, m), 2.66 (1H, dd, J=5.4, 13.7 Hz), 2.49
(1H, dd, J=9.0, 13.7 Hz), 2.34 (3H, s), 2.12–2.03 (2H,
m), 1.92–1.51 (8H, m), 1.14 (3H, d, J=6.3 Hz), 1.06 (3H,
d, J=5.6 Hz), 0.96 (3H, d, J=6.3 Hz), 0.91 (6H, d,
J=7.0 Hz).
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Merino, P.; Tejero, T. J. Org. Chem. 1997, 62, 5497.
.