A convergent synthesis approach towards CGP60536B, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate

Article abstract of DOI:10.1016/S0040-4039(00)01794-9

We report a convergent synthesis of the potent orally active non-peptide renin inhibitor CGP60536B. The key reaction employs the coupling of the enantiopure Grignard species derived from chloride 13 with the diastereomerically pure γlactone 9b. The stereoselective reduction of the resulting ketone 14b has been thoroughly investigated. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01794-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10085–10089
A convergent synthesis approach towards CGP60536B, a
non-peptide orally potent renin inhibitor, via an
enantiomerically pure ketolactone intermediate
Heinrich Ru¨eger,a Stefan Stutz,a Richard Go¨schke,a Felix Spindlerb and Ju¨rgen Maibauma,*
aNovartis Pharma AG, Metabolic and Cardiovascular Diseases, Klybeckstrasse 220, CH-4002 Basel, Switzerland
bNovartis Services AG, CH-4002 Basel, Switzerland
Received 25 August 2000; revised 3 October 2000; accepted 11 October 2000
Abstract
We report a convergent synthesis of the potent orally active non-peptide renin inhibitor CGP60536B.
The key reaction employs the coupling of the enantiopure Grignard species derived from chloride 13 with
the diastereomerically pure g-lactone 9b. The stereoselective reduction of the resulting ketone 14b has been
thoroughly investigated. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: renin inhibitor; Grignard reaction; g-butyrolactone derivatives; keto-lactone; stereoselective hydrogenation.
The highly potent, orally active human renin inhibitor CGP60536B (1), one of a novel class
of dipeptide transition state mimetics, exerted a pronounced and long-lasting blood-pressure
reduction in marmoset monkeys and has been selected for clinical investigation.1
The initial synthetic route to the hydroxyethylene isostere 1, which followed the classical
protocol2 via a non-proteinogenic N-BOC a-amino acid intermediate, had major disadvantages
such as a high number of linear steps and insufficient stereoselectivity for key reaction steps,
and thus was not amenable for scale-up.1 Aiming at a more convergent approach, the
Grignard addition of the readily accessible fragment A to a suitable g-butyrolactone precursor
B was envisaged as an attractive route resulting from retrosynthetic cleavage of the C5ꢀC6
bond of 1 (Scheme 1). We report here the synthesis of the keto-lactone precursor 14b as single
diastereoisomer,3 as well as our studies on its stereoselective reduction and subsequent conver-
sion to 1.
* Corresponding author. E-mail: juergen klaus.maibaum@pharma.novartis.com
–
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01794-9

10086
Scheme 1.
For initial rapid exploration of this alternative synthetic pathway we devised a practical
method for the preparation of the diastereopure g-butyrolactone acid 8 on a multi-gram scale
(Scheme 2). Dihydroxylation,4 of the oxazolidinone 3,5 cleavage of the auxiliary and lactonisa-
tion provided alcohol 4 as a 1.6:1 ratio of the inseparable 2(R),4(S):2(R),4(R)-diastereomers.
Sharpless oxidation was employed to convert 4 to the benzylic esters 6 and 7, which were easily
separated by SC chromatography. Hydrogenation of the more polar 7 afforded the desired acid
8 and subsequently 9b, which was purified by distillation (bp 64–65°C, 0.06 mbar) without
detectable epimerisation.6 Attempts to prepare aldehyde 10 by various oxidation methods were
unsuccessful.3
Scheme 2. Reagents: (a) LiHMDS, allyl bromide, THF, −78°C, 94%; (b) OsO4 (cat.), NMMO, tert-BuOH–acetone–
H2O (1:1:1), 88%; (c) NaIO4, RuCl3·H2O, CCl4–MeCN–H2O (1:1:2), 6 h, >78%; (d) (COCl)2, toluene, DMF (cat.), 1
h, 80–85%; (e) BnOH, NEt3, CH2Cl2, 82% (combined yield); (f) flash chromatography on silica gel; (g) 7, H2, Pd/C
10%, EtOAc, 100%
Alkyl chloride 13, readily synthesized from enantiopure acid 111 after reduction to the alcohol
12 and chlorination with SOCl2/pyridine, was transformed smoothly into the Grignard reagent
which reacted with the enantiomeric acid chloride 9a8 to provide the keto-lactone 14a (Scheme
3) in good yield. In case of 9b bearing the 2(R)-isopropyl group, improved yields (ca. 90%) were
obtained by addition of an excess of the Grignard species (1.5 equiv.) to afford 14b as crystalline
solid after chromatographic removal of the homo-coupling side product. No epimerisation9 at
the carbon adjacent to the keto group was observed.10
The diastereoselective reduction of the ketones 14 to the desired alcohols 1%(R)-15 as the key
step was thoroughly investigated (Table 1). The initial results from the standard reaction of 14a
with NaBH4 giving an appreciable (3:1)-diastereoselectivity for 1%(R)-15a versus 1%(S)-16a
(chelation control, cf. Ref. 9) were promising (entry 1). However, in the case of 14b bearing the
2(R)-isopropyl group (entry 2, vide infra for configurational assignment) diastereofacial differen-
tiation was only minor and opposite under the same conditions. On the other hand, excellent
diastereoselectivities were observed with the bulky K-selectride®9 affording almost exclusively
1%(R)-16a, as well as the undesired 1%(R)-16b (Felkin-Ahn products, entries 3, 4). Also, pressure

10087
Scheme 3. Reagents: R1=CH3O(CH2)3ꢀ: (a) NaBH4, I2, THF, 4 days rt, 90%; (b) SOCl2, Py, CHCl3, 70%; (c) 13, Mg,
BrCH2CH2Br, THF, rt; (d) see Table 1 for details; (e) MsCl, NEt3, CH2Cl2, 82–99%; (f) NaN3, 15-crown-5, DMPU,
85%; (g) H2NCH2C(Me)2CONH2 (21), 2-OH-pyridine, NEt3, 59%; (h) H2, Pd/C MeOH, 74%; (i) NH2OH·HCl,
NaHCO3, MeOH, rt, 81%; (j) NH2OBn·HCl, NaHCO3, 89%; (k) H2, Pd/C, 1N HCl, MeOH
Table 1
Diastereoisomeric ratios for the reduction of keto-lactones 14a,b
Entry
Substrate
Reducing agent/catalysta
Reaction conditions
Ratiob
% Yieldc
15a/b:16a/b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
14a
14b
14a
14b
14a
14a
14b
14b
14b
14b
14b
14b
14b
14b
NaBH4
NaBH4
K-Selectride
K-Selectride
THF/EtOH 1:2, rt
MeOH, rt
THF, −78“0°C
THF, −78°C
THF, rt
3:1
98
89
84
70–80
35
1:1.1
3:97d
3:97
1:1
1:3
No reaction
1.3:1
1.1:1
1.5:1
1:1
1:1
1:100
1:1.5
BH3, Me2S
BH3/(S)-Oxazaborolidine
Rh°/bppfoh
Rh°/(R)-(S)-cy2PFꢀPcy2
Rh°/(S)-(R)-cy2PFꢀPcy2
Rh°/(R)-(S)-PPFꢀPcy2
Rh°/(R)-(S)-PPFꢀP(xyl)2
Rh°/(R)-(S)ꢀPPFꢀP(tert-Bu)2
[Ru2Cl4((S)-BINAP)]NEt3
[Ru2Cl4((R)-BINAP)]NEt3
THF, −10“0°C
64
–
H2, MeOH, 50 bar, rt
H2, toluene, 50 bar, rt
H2, toluene, 50 bar, rt
H2, toluene, 80 bar, rt
H2, toluene, 80 bar, rt
H2, toluene, 80 bar, 40°C
H2, MeOH, 50 bar, 40 h
H2, MeOH, 50 bar
Nde
Nd
Nd
Nd
Nd
41
Nd
a see Ref. 16.
b Determined by RP-HPLC, Nucleosil C18, 5 mm, MeCN (Gradient 20–100% within 20 min)–water.
c Isolated yields, conditions not optimized.
d Stereochemical assignment according to Ref. 9.
e Not determined.

10088
hydrogenation using Noyori’s Ru-BINAP catalyst11 (entry 13) provided exclusively 16b when the
(S)-complex was used (matched stereodifferentiation). In contrast, the (R)-BINAP complex (entry
14) was non-selective. The Rh–PP chiral complexes in entries 8, 10 were the only Rh catalysts
leading to the desired 15b in slight excess, however, the observed minor stereoinduction was not
promising for further optimisation.
Assignment of the absolute configuration of the pure epimers 15b and 16b, obtained both in
gram quantities from NaBH4 reduction of 14b and separation by silica gel flash chromatography,
was established by their straightforward conversion to 1 and the 5(R)-isomer 18, respectively
(Scheme 3). Thus, displacement of the corresponding mesylates of 15b and 16b with sodium azide
in the presence of catalytic 15-crown-5 occurred with complete inversion to provide 1%(S)-
configured azido-lactone 17a and its 1%(R)-epimer 17b. Direct opening of lactone 1%(S)-17a with
amine 21, which turned out to be only a weak nucleophile, required addition of stoichiometric
2-OH-pyridine.12,13 Final reduction of the azide group afforded a product which was identical by
proton NMR with the target compound 1, and which was clearly distinguishable from epimer
18 obtained from 17b.
We also sought to introduce the nitrogen group stereoselectively via the oximes 19 and 20, both
obtained from 14a as E/Z isomers (1:1) in high yields (Scheme 3). All attempts to reduce 19 with
borohydrides or by catalytic hydrogenation under neutral or acidic conditions failed, and
hydrogenation (Pd/C) of 20 led exclusively to O-debenzylation.14 Also, 20 was inert towards
NaBH4 under standard conditions, and in the presence of a large excess of the reagent concomitant
reduction to the O-benzyl hydroxylamine and of the lactone to the lactol was observed.15
In summary, a convergent practical synthesis of the stereoisomerically pure keto-lactone 14b
as precursor of the novel renin inhibitor CGP60536B (1) has been devised. Attempts to reduce
14b stereoselectively to the desired alcohol 1%(R)-15b, which was transformed with complete
inversion to azide 17a, remained unsuccessful. On the other hand, reduction with K-selectride®
or hydrogenation in presence of [Ru2Cl4((S)-BINAP)]NEt3 proceeded in a highly diastereofacial
manner to give alcohol 1%(S)-16b which could potentially provide access to 1 via a double-inversion
protocol. Moreover, the present work and continued efforts to establish a stereoselective synthesis
of g-butyrolactone 9b led to a new efficient large-scale synthesis of 1 which is reported elsewhere.3
Acknowledgements
We thank Mr. Paul Richert, Novartis Pharma Research, for the chiral HPLC analyses of the
keto-lactone intermediates and Ms. Cecile Rochat and Ms. Nicole Hasler for the excellent technical
assistance.
References
1. Maibaum, J.; Stutz, S.; Go¨schke, R.; Rigollier, P.; Yamaguchi, Y.; Schilling, W.; Wood, J. M. XVth EFMC
International Symposium on Medicinal Chemistry; Edinburgh (UK), 6–10 September 1998, Abstract Book, p. 230.
2. Holladay, M. W.; Salituro, F. S.; Rich, D. H. J. Med. Chem. 1987, 30, 374–383.
3. Sandham, D. A.; Taylor, R. J.; Carey, J. S.; Fa¨ssler, A. Tetrahedron Lett. 2000, 41, 10091–10094.
4. Asymmetric dihydroxylation of the N,N-disubstituted carboxamide 3 using the modified AD-mix-b reagent (cf.
Bennani, Y. L.; Sharpless, B. K. Tetrahedron Lett. 1993, 2079–2082) was unsuccessful, resulting in a 1:1 mixture
of diastereomers 4.

10089
5. Prepared according to Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737–1739.
6. Assignment of the absolute configuration of 8 and 9b was accomplished by derivatizing 4 to the known silyl
ethers 21 and 22.7 Compound 8 prepared from the less polar 22 (Rf=0.53, hexane–methyl tert-butyl ether 3:1)
was identical by NMR to the material obtained according to Scheme 2: Colorless oil, [h]2D2=−9.6 (c=1, CH2Cl2),
1H NMR (CDCl3): l 8.0 (br. s, 1H), 4.92 (dd, J=11.3, 7.5 Hz, 1H), 2.73–2.58 (m, 1H), 2.46–2.34 (m, 2H), 2.20
(m, 1H), 1.04 (d, J=12 Hz, 3H), 0.94 (d, J=12 Hz, 3H) ppm. The 1H NMR of the 1(R),3(R)-epimeric acid
prepared from 6 showed a signal at 4.86 ppm (dd, J=15.1, 11.3 Hz) for the C1 methine.
Reagents: (a) TBDPSiCl, imidazole, DMF, rt, 12 h, 97%; (b) separation of diastereomers on silica gel; (c) 22,
TBAF, THF, 73%; (d) NaIO4, RuCl.3H2O, CCl4–MeCN–H2O (1:1:2), 6 h, 96%.
7. Hanessian, S.; Abad-Grillo, T.; McNaughton-Smith, G. Tetrahedron 1997, 53, 6281–6294.
8. Mori, K. Tetrahedron 1975, 31, 3011–3012.
9. Larcheˆveque, M.; Lalande, J. J. Chem. Soc., Chem. Commun. 1985, 83–84.
10. Compound 14b and the corresponding epimer prepared in a similar manner from 7 (Scheme 2) could be
completely separated by chiral HPLC using a Chiradex® column with 30:70 MeOH/triethylamine acetate 0.5%
(pH 5.6) as eluant. The Grignard reaction of the acid chloride derived from 6 proceeded much more slowly and
gave lower product yields as compared with the corresponding epimeric 9b with 2(R)-9b proceeded much slower
and gave lower product yields as compared to 2(S)-9b.
11. Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Inoue, S.; Kasahara, I.; Noyori, R. J. Am.
Chem. Soc. 1987, 109, 1596.
12. Openshaw, H. T.; Whittaker, N. J. Chem. Soc. (C.) 1969, 89.
13. A more detailed account of this work will be reported elsewehere.
14. Reduction of 19 with Bu3P, PhSSPh following Barton’s protocol gave a 1:1 mixture of 1 and 18 in 50% yield (J.
S. Carey, personal communication): Barton, D. H. R.; Motherwell, W. B.; Simon, E. S.; Zard, S. J. Chem. Soc.,
Perkin Trans. 1 1986, 2243–2252.
15. For the diastereospecific reduction of bulky, bridged orthoester O-benzyloximes and their ring-open congeners
with borohydrides, see: Dequeker, E.; Compernolle, F.; Toppet, S.; Hoornaert, G. Tetrahedron 1995, 51,
5877–5890.
16. The chiral catalysts have the following structure:
.
.