Practical synthesis of a renin inhibitor via a diastereoselective dieckmann cyclization

Article abstract of DOI:10.1021/ol102131e

A scalable synthesis of a potent renin inhibitor (1) is described. The absolute stereochemistry is set via an unprecedented diastereoselective Dieckmann cyclization directed by a remote chiral protecting group. This transformation enables preparation of chiral 1,3-[3.3.1]-diazabicyclononenes by desymmetrization of alkyl-esters, with selectivities ranging from 4 to 17:1.

Full text of DOI:10.1021/ol102131e

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5146-5149
Practical Synthesis of a Renin Inhibitor
via a Diastereoselective Dieckmann
Cyclization
Danny Gauvreau,* Greg J. Hughes, Stephen Y. W. Lau, Daniel J. McKay,
Paul D. O’Shea, Rick R. Sidler, Bing Yu, and Ian W. Davies
Merck Frosst, Centre for Therapeutic Research, Department of Process Research,
16711 TransCanada Highway, Kirkland, Que´bec, Canada, H9H 3L1
danny_gauVreau@merck.com
Received September 7, 2010
ABSTRACT
A scalable synthesis of a potent renin inhibitor (1) is described. The absolute stereochemistry is set via an unprecedented diastereoselective
Dieckmann cyclization directed by a remote chiral protecting group. This transformation enables preparation of chiral 1,3-[3.3.1]-
diazabicyclononenes by desymmetrization of alkyl-esters, with selectivities ranging from 4 to 17:1.
The renin-angiotensin system (RAS) is known to play an
important role in cardiovascular diseases, renal diseases, and
metabolic disorders.1,2 Renin is an aspartyl protease that
cleaves angiotensinogen to a decapeptide angiotensin I. This
substrate is then further cleaved by the angiotensin-converting
enzyme (ACE) to an octapeptide angiotensin II, a substance
identified as a powerful vasoconstricting peptide. Recently,
renin has been validated as a target in the regulation of high
blood pressure and heart failure.3
for the preparation of multigram to kilogram quantities.
While a racemic synthesis of 1 has been reported,4 there are
no reports of a stereoselective approach to the chiral 1,3-
[3.3.1]-diazabicyclononene core. We describe herein a practi-
cal stereoselective synthesis of 1 via an unprecedented
diastereoselective Dieckmann cyclization, directed by a
remote protecting group.5
Our retrosynthetic approach is outlined in Scheme 1. We
envisioned that 1 could be assembled via an amide coupling
between benzyl amine 2 and bicyclic acid 3, followed by
deprotection of both amines. Acid 3 could be obtained from
the Suzuki cross-coupling between tosylate 4 and aryl
boronate ester 5 to allow for a convergent approach. Finally,
MK-8141 (1) is a potent and selective, orally bioavailable
renin inhibitor.4 To support further development of this
compound, we needed to develop a scalable synthesis suitable
(1) Skeggs, L. T.; Dovens, F. E.; Levins, M.; Lentz, K.; Kahn, J. R.
The Renin-Angiotensin System; Jonhson, J. A., Anderson, R. R., Eds.;
Plenum Press: New York, 1980; p 1. MacGregor, G. A.; Markandu, N. D.;
(4) Bezenc¸on, O.; Bur, D.; Weller, T.; Richard-Bildstein, S.; Remen,
L.; Sifferlen, T.; Corminboeuf, O.; Grisostomi, C.; Boss, C.; Prade, L.;
Delahaye, S.; Treiber, A.; Strickner, P.; Binker, C.; Hess, P.; Steiner, B.;
Fischli, W. J. Med. Chem. 2009, 52, 3689–3702.
Roulston, J. E.; Jones, J. C.; Morton, J. J. Nature 1981, 291, 329–331
.
(2) For recent reviews, see: Carey, R. M.; Stragy, H. M. Endocr. ReV.
2003, 24, 261–271. Persson, P. B. J. Physiol. 2003, 552, 667–671. Re, R. N.
Med. Clin. North Am. 2004, 88, 19–38. Brewster, U. C.; Perazella, M. A.
Am. J. Med. 2004, 116, 263–272. Aneja, A.; El-Atat, F.; McFarlane, S. I.;
(5) To the best of our knowledge, this type of desymmetrizing
diastereoselective Dieckmann approach has not been previously disclosed
in the literature. For a conceptually distinct diastereoselective Dieckmann
approach, see: (a) Boger, D. L.; McKie, J. A.; Nishi, T.; Ogiku, T. J. Am.
Chem. Soc. 1997, 119, 311. (b) Groth, U.; Kesenheimer, C.; Kreye, P. Synlett
2006, 14, 2223. (c) Kawabata, T.; Watanabe, T. Heterocycles 2008, 76,
1593.
Sowers, J. R. Recent Prog. Horm. Res. 2004, 59, 169–205
.
(3) Maibaum, J.; Stutz, S.; Goschke, R.; Rigollier, P.; Yamagushi, Y.;
Cumin, F.; Rahuel, J.; Baum, H. P.; Cohen, N. C.; Schnell, C. R.; Fuhrer,
W.; Gruetter, M. G.; Schilling, W.; Wood, J. M. J. Med. Chem. 2007, 50,
4832–4844.
10.1021/ol102131e  2010 American Chemical Society
Published on Web 10/14/2010

t
Treatment of 6 with BuOK in toluene at 100 °C afforded
complete conversion to the racemic Dieckmann cyclization
product. We postulated that this strategy could be used with
control of the absolute stereochemistry if a chiral amine
replaced methylamine. Ideally, this amine would be easily
installed and deprotected while being effective at inducing
stereoselectivity in the subsequent base-mediated Dieckmann
cyclization. Given the unprecedented nature of its potential
enantiocontrol, this amine would have to be readily available
in either antipode to maximize our probability of aquiring
either diastereomer. On the basis of these criteria, we initially
turned our attention to R-methylbenzyl amine which is
available in bulk quantities at <$50/kg for either the S or R
enantiomers and should be susceptible to straightforward
removal by hydrogenolysis.
Scheme 1. Retrosynthic Approach to Renin Inhibitor 1
Prior to the evaluation of the diastereoselective Dieckmann
cyclization, we needed to develop an efficient synthesis of
piperazines 6. The reported conditions used to prepare 6a
(R ) Me) afforded <10% of the desired adduct 6c after 24 h
upon direct replacement of methylamine with an excess of
(R)-methylbenzyl amine. Performing the reaction neat at 80
°C improved the yield of 6c to 30% with modest selectivity
(4:1) for the desired cis isomer. After an extensive solvent
screen, we were pleased to find that running the reaction in
a minimal amount of 1,1,1-trifluoroethanol (3 mL/g) in the
presence of only 3 equiv of (R)-methylbenzyl amine allowed
for the piperazine to be isolated in 80% yield as a 20:1
mixture of cis:trans isomers.6 This protocol was also
successful for the preparation of a series of analogous chiral
alkyl aryl protected piperazines 6a-f (Table 1).
we imagined that the absolute stereochemistry of the bicyclic
core could be installed via an unprecedented diastereoselec-
tive Dieckmann cyclization of piperazine 6. To do so, we
hypothesized that using a remote chiral protecting group on
the bridged amine could direct the base-mediated cyclization.
The piperazine 6 could be formed from a double 1,4-addition
of a chiral amine 7 to the R,ꢀ-unsaturated ester 8.
In the reported racemic synthesis of 1,4 piperazine 6 (R
) Boc, R* ) Me) was prepared by double-Michael addition
of methyl amine to readily available dieneoate 8 (R ) Bn)
affording a 1.5:1 mixture of trans and cis (desired) 6 isomers.
Table 1. Double-Michael Addition of Chiral Amines and Diastereoselective Dieckmann Cyclization Results
c
a All reactions were performed at 20 °C in 1,4-dioxane. b dr measured by HPLC. Reaction performed using AmOK at -25 °C in DMF. The use of
t
tBuOK in 1,4-dioxane lead to a 6:1 dr, 78% yield.
Org. Lett., Vol. 12, No. 22, 2010
5147

With a reasonable synthesis of the piperazines in hand,
efforts were undertaken to identify effective conditions for
stereoselective Dieckmann cyclization using 6c as a model
substrate. The initial reaction conditions evaluated were those
used in the racemic synthesis of 1 (NaH, in THF at 45 °C).4
We were pleased that under these conditions a promising
3:1 diastereoselectivity of the desired bicycle 4c was
obtained. In constrast to the reactivity of 6a which required
5 h to obtain complete conversion at 45 °C in THF, complete
conversion with 6c was achieved after only 30 min. Perform-
ing the reaction at ambient temperature improved the
6b failed to undergo cyclization even under forcing condi-
tions (refluxing toluene).10
t
diastereoselectivity to 6:1, when BuOK was used as base.
Figure 1. Preferential configuration of 6c as observed by X-ray
crystallography.
An evaluation of solvent, base, and temperature revealed that
performing the Dieckmann cyclization at -25 °C in DMF
improved the diastereoselectivity up to 8.5:1 in the presence
t
of 2.1 equiv of AmOK (allowing the internal temperature
These studies shed some light on the observed sense
of diastereoselectivity. In particular, the computational
studies suggest hindered rotation about the N1 (bridged-
nitrogen)-C5 (carbon of the chiral center) bond of 3.5 kcal
with the C5-bound proton being oriented to minimize gauche
interactions between the bulkier C5 substituents and the
axially oriented acetate groups (Figure 1). This orientation
results in a preferential shielding of one of the methylene
groups by the bulkier phenyl group with the other methylene
proximal to the methyl group and thus more exposed. While
it is tempting to suggest that the sense of selectivity derives
from the selective deprotonation of the more accessible
proton, attack of this enolate on the more hindered ester
would lead to the minor diastereomer. Further studies are
required to determine the mechanism of this transformation
and will be conducted in due course.11
The end game of the synthesis required cross coupling of
tosylate 4c with a suitable coupling partner derived from aryl
bromide 9. Following extensive investigation, it was deter-
mined that Suzuki-type cross coupling was optimal. Aryl
boronate 5 was accessed via trans-metalation of the aryl
bromide 912 to the corresponding triaryl lithium magnesiate13
followed by quenching of this intermediate with trimethyl
borate. Treatment of the resulting boronate ester 5 with 2
mol % PdCl2, dppb, and the bismesylate salt of 4c yielded
10 in 92% yield, isolated as its bis-HCl salt (Scheme 2).
The ester moiety of 10 proved difficult to hydrolyze under
standard saponification conditions.14 Although the use of
excess potassium trimethylsilanolate did give a high yield
of 3a, a cheaper alternative was desired. An investigation
of hydrolysis conditions revealed that treatment of 10 with
excess potassium tert-butoxide (7 equiv) in tert-butanol at
50 °C gave 3a in 93% yield. Activation of this acid using
to reach -5 °C over 2 h to achieved complete conversion),
with an HPLC assay yield of 90%. Conveniently, the keto-
ester was immediately trapped with tosyl anhydride to afford
the tosylate required for the next step.
As outlined in Table 1, additional chiral R-alkyl-aryl
amines were investigated to explore the effect of the chiral
substituent on the selectivity of the Dieckmann cyclization.
Increasing the size of the aryl versus the alkyl substituent
had an opposite effect on the selectivity. The presence of a
bulkier aryl group (2-naphtyl, 6d, entry 4) improved the
diastereoselectivity of the Dieckmann (17:1 ratio),7 while
the use of a more hindered alkyl group (R-ethylbenzyl, 6e,
entry 5) led to lower selectivities (4:1).
Interestingly, the use of methyl-protected S-phenylglyci-
nols (entry 6, 6f) lead to a slightly higher selectivity (11:1).
Although these chiral amine substituents did afford higher
levels of selectivity, weighing these modest improvements
against the lower yields and higher cost of these amines made
the use of R-(R)-methylbenzyl amine a superior selection. It
is noteworthy that the addition of 2 equiv of methane sulfonic
acid to the crude workup stream allowed for the bismesylate
salt of 4c which was isolated in 63% yield from 6c and
greater than 99:1 dr.
The unexpectedly high rate of reaction observed for the
R-methylbenzyl-substituted compounds can be explained if
the ester groups were fixed in a diaxial orientation. This is
plausible if one invokes strain akin to the A1,3 allylic strain
observed with analogous 2,6-disubstituted N-Boc protected
piperidines which are well-known to adopt such a conforma-
tion.8 In support of this assertion, both computational and
crystallographic studies show the preference for diaxial
orientation of the ester functionalities of 6c (Figure 1).9
Interestingly, the unsubstituted benzyl-protected compound
(10) Ho, T.-L.; Lin, Y.-J. J. Chin. Chem. Soc. 1997, 44, 261. Ho and
Line have found Dieckmann cyclizations of analogous N-benzyl thiomor-
pholine substrates to be similarly challenging.
(6) It is believed that the acidity of the 1,1,1-trifluoroethanol allows for
an easier proton exchange during the Michael addition.
(7) The 1-naphthyl susbtrate could not be evaluated in the Dieckmann
cyclization since the double-Michael addition failed using (1-naphthyl)-
ethylamine.
(11) Two plausible pathways allow to access the major diastereomer:
(a) selective deprotonation of the less hindered methylene, followed by
ketene formation, then deprotonation of the more hindered methylene and
cyclization on the ketene; or (b) selective deprotonation of the less hindered
methylene, followed by proton-transfer and cyclization.
(8) Johnson, F. Chem. ReV. 1968, 68, 375. Quick, J.; Mondello, C.;
Humora, M.; Brennan, T. J. Org. Chem. 1978, 43, 2705. Neipp, C.; Martin,
S. F. J. Org. Chem. 2003, 68, 8867.
(12) Gauvreau, D.; Huffman, M. A.; Hughes, G.; Itoh, T.; Yin, J.; Lau,
S.; O’Shea, P. WO 2008088690 A2. July 24, 2008.
(13) Lau, S. Y. W.; Hughes, G.; O’Shea, P. D.; Davies, I. W. Org. Lett.
2007, 9, 2239.
(9) See Supporting Information for X-ray and computational calculation
data.
(14) No hydrolysis occurred using excess LiOH(aq) in THF at 67 °C.
5148
Org. Lett., Vol. 12, No. 22, 2010

using Pd(OH)2 under hydrogen atmosphere (200 psi). In this
reaction, the presence of zinc bromide was key to avoid
proto-dechlorination.15 Following workup, 1 was isolated as
its bis-MsOH salt in 71% yield with high purity, with
spectroscopic properties and specific rotation matching those
of an authentic sample.16
Scheme 2. Completion of the Synthesis of 1
In conclusion, we have developed a practical stereoselec-
tive synthesis of renin inhibitor MK-8141 in 9 steps and
23% overall yield from benzyl amine, without silica gel
chromatography. The absolute stereochemistry is introduced
by the use of a remote chiral auxiliary which directs an
unprecedented diastereoselective Dieckmann cyclization.
Acknowledgment. We thank Dr. Richard G. Ball and
Nancy N. Tsou (Merck Process Research, Rahway) for their
support in X-ray crystallography.
Supporting Information Available: Procedures and
spectra of compounds 1·2MsOH, 2, 3a, 4c-4f, 6a-6f, 9,
10·2HCl, and 11. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL102131E
(15) Wu, G.; Huang, M.; Richards, M.; Poirier, M.; Wen, X.; Draper,
R. W. Synthesis 2003, 11, 1657.
oxalyl chloride and catalytic DMF followed by amidation
with amine 2 afforded 11 in 73% yield. The synthesis was
completed by a global deprotection of the benzyl groups
(16) The use of (S)-R-methylbenzylamine lead to the preparation of the
opposite enantiomer of MK-8141.
Org. Lett., Vol. 12, No. 22, 2010
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