functionalization of the double bond, followed by amide
formation and hydrogenolysis at the benzylic site, would
produce aliskiren or its congeners5a depending on the nature
of substituent R in the aromatic moiety. The feasibility of
this highly stereocontrolled approach was put to the test,
being cognizant of the challenges of effecting the seldom
explored RCM reaction to produce a nine-membered lactone
such as E16 and developing strategies for the projected regio-
and stereoselective introduction of the vicinal amino alcohol
moiety in the target molecule.
Extensive studies with various organometallic reagents
prepared from 1 led to the mixed organomagnesiate reagent
217 as the preferred reacting partner to enantioenriched aldehyde
A,13 furnishing the (R,S)-isomer 3 as the major product (Scheme
1). Ester formation with B produced an 8:1 mixture of esters
in which the (S,R,S)-isomer 4 was predominant as determined
by NMR. Treatment of this mixture with 5 mol % of Grubbs
first-generation catalyst15b in the presence of Ti(O-i-Pr)415c in
toluene at 10 mM concentration led to the lactone 5 as a single
diastereoisomer in 81% yield.18 Aziridination using Du Bois’
elegant catalytic method19 produced 6 in 75% yield. At this
juncture, its relative stereochemistry was based on the results
of a diastereoselective dihydroxylation reaction of the p-
methoxyphenyl congener (Scheme 2). When lactone 6 was
subjected to TFA in dichloromethane, a remarkably smooth one-
step formation of a pyrrolidine lactone took place to afford 7
in 85% yield. A plausible pathway, shown for the p-methox-
yphenyl congener in Scheme 3, most likely involves the
formation of a benzylic cation stabilized by the p-methoxyphe-
nyl group,20 thereby releasing the carboxylic acid, which effects
an intramolecular opening of the N-trichloroethylsulfamoyl
aziridine ring with inversion of configuration. This is followed
by a stereocontrolled attack of the sulfamate nitrogen on the
benzylic cation (or its quinonoid equivalent) to give the lactone
14 (or 7 in the case of 6).
Figure 1
aliskiren.
. Retrosynthetic analysis of the “macrocycle route” toward
These were then used for convergent assemblies in a series
of multiple operations en route to aliskiren.
We report herein a stereocontrolled and original synthesis
of aliskiren, comprising 11 unoptimized linear steps in an
overall yield of 7%. Our “macrocycle route” to aliskiren is
shown in Figure 1, where a (2S)-2-isopropyl-4-pentenal A,
obtained directly by application of MacMillan’s iminium
catalysis protocol12,13 or from oxidation of the corresponding
alcohol14 is converted to intermediate C. Ester formation with
carboxylic acid B, prepared by oxidation of A, or by an
Evans allylation,14 would afford D. Ring-closing metathesis15
would lead to the nine-membered lactone E. Regioselective
In spite of documented precedents for analogous com-
pounds,7,8 amide formation with the highly hindered 3-amino-
2,2-dimethylpropionamide (ADPA) from lactone 7 was
problematic, affording the amide 8 in modest yield (61%
based on 27% of recovered starting lactone). This was
transformed to the known N-Boc-pyrrolidine amide 98a in
60% yield over two steps. After much experimentation, it
(7) (a) Herold, P.; Stutz, S.; Spindler, F. WO 0202508, 2002. (b) Herold,
P.; Stutz, S. WO 0202500, 2002. (c) Herold, P.; Stutz, S. WO 0202487,
2002. To the best of our knowledge, catalytic asymmetric hydrogenation
of (()-R-isopropylcinnamic acid was used by the Speedel group in the
synthesis of an intermediate towards aliskiren; see also: Boogers, J. A. F.;
Felfer, U.; Kotthaus, M.; Lefort, L.; Steinbauer, G.; de Vries, A. H. M.; de
Vries, J. G. Org. Proc. Res. DeV. 2007, 11, 585.
(14) (a) Evans, D. A.; Britton, T. C.; Dorrow, R. L.; Dellaria, J. F., Jr.
Tetrahedron 1988, 44, 5525. See also: (b) Hodgson, D. M.; Foley, A. M.
J. Chem. Soc., Perkin Trans. 1 1999, 2911. (c) Hodgson, D. M.; Boulton,
L. T.; Lovell, P. J.; Maw, G. M. Synlett 1999, 744. (d) Paquette, L. A.;
Guevel, R.; Sakamoto, S.; Kim, I. H.; Crawford, J. J. Org. Chem. 2003,
68, 6096.
(8) (a) Mickel, S. J.; Sedelmeier, G.; Hirt, H.; Scha¨fer, F.; Foulkes, M.
WO 2006131304, 2006 . (b) Maibaum, J.; Stutz, S.; Go¨schke, R.; Rigollier,
P.; Yamaguchi, 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. (c) Ru¨eger, H.; Stutz, S.; Go¨schke, R.;
Spindler, F.; Maibaum, J. Tetrahedron Lett. 2000, 41, 10085. (d) Sandham,
D. A.; Taylor, R. J.; Carey, J. S.; Fa¨ssler, A. Tetrahedron Lett. 2000, 41,
10091.
(15) (a) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, 2003; Vols. 1-3. (b) Schwab, P.; Grubbs, R. H.; Ziller, J. W.
J. Am. Chem. Soc. 1996, 118, 100. (c) Fu¨rstner, A.; Langemann, K. J. Am.
Chem. Soc. 1997, 119, 9130.
(16) For reviews, see: (a) Shiina, I. Chem. ReV. 2007, 107, 239. (b)
Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199.
(17) Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org. Chem.
2001, 66, 4333.
(9) Dondoni, A.; De Lathauwer, G.; Perrone, D. Tetrahedron Lett. 2001,
42, 4819.
(18) The minor (S,S,S)-diastereoisomer did not cyclize under the reaction
conditions, possibly due to a steric interaction of the phenyl ring with the
adjacent syn-oriented 2-isopropyl group. It could be recovered as the major
product, in addition to a minimal amount of unreacted (S,R,S)- isomer. The
use of other catalysts is under study.
(10) Lindsay, K. B.; Skrydstrup, T. J. Org. Chem. 2006, 71, 4766.
(11) Dong, H.; Zhang, Z.-L.; Huang, J.-H.; Ma, R.; Chen, S.-H.; Li, G.
Tetrahedron Lett. 2005, 46, 6337.
(12) For example, see: Besson, T. D.; Mastracchio, A.; Hong, J.-B.;
Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582.
(13) See the Supporting Information.
(19) Guthikonda, K.; Du Bois, J. J. Am. Chem. Soc. 2002, 124, 13672.
(20) For example, see: Cozzi, P. G.; Benfatti, F. Angew. Chem., Int.
Ed. 2009, 48, 1313.
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