Asymmetric hydrogenation of protected allylic amines

Article abstract of DOI:10.1021/ol101804e

A general method for the enantioselective hydrogenation of protected allylic amine derivatives is described. This procedure relies on the generation of a cationic ruthenium complex with the axially chiral ligand (-)-TMBTP. The utility is highlighted by th

Full text of DOI:10.1021/ol101804e

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4201-4203
Asymmetric Hydrogenation of Protected
Allylic Amines
Dietrich P. Steinhuebel,* Shane W. Krska,* Anthony Alorati, Jenny M. Baxter,
Kevin Belyk, Brian Bishop, Michael Palucki, Yongkui Sun, and Ian W. Davies
Department of Process Research, Merck & Co. Inc., PO Box 2000,
Rahway, New Jersey 07065, and Department of Process Research, Merck Sharp and
Dohme Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, U.K.
dietrich_steinhuebel@merck.com; shane_krska@merck.com
Received August 6, 2010
ABSTRACT
A general method for the enantioselective hydrogenation of protected allylic amine derivatives is described. This procedure relies on the generation
of a cationic ruthenium complex with the axially chiral ligand (-)-TMBTP. The utility is highlighted by the highly enantioselective hydrogenation of
a diene substrate that can then be elaborated to prepare Telcagepant, a compound currently in Phase III clinical trials. The scope of the hydrogenation
reaction was studied, and a variety of substituted allylic amine derivatives could be hydrogenated with enantiomeric ratios of 92:8 or higher.
Telcagepant is an antagonist of the calcitonin gene-related
peptide (CGRP) receptor currently in Phase III clinical trials
Scheme 1. Retrosynthesis of Telcagepant
and has the potential to become a novel therapy for the
treatment of migraine headaches (Scheme 1).1
Although caprolactams are core structures in several phar-
maceutical agents, the novel trans stereochemistry and trifluo-
roethylated amide of telcagepant represent significant synthetic
challenges in the development of an efficient scalable synthesis.2
We envisioned a synthesis of caprolactam 1 proceeding via an
asymmetric hydrogenation of differentially protected diene 2
(Scheme 1). While the enamide hydrogenation is well prece-
(1) Paone, D. V.; Shaw, A. W.; Nguyen, D. N.; Burgey, C. S.; Deng,
Z. J.; Kane, S. A.; Koblan, K. S.; Salvatore, C. A.; Hershey, J. C.; Wong,
B.; Roller, S. G.; Miller-stein, C.; Graham, S. L.; Vacca, J. P.; Williams,
T. M. J. Med. Chem. 2007, 50, 5564–5567.
dented, reports of a general catalyst system for the asymmetric
hydrogenation of trisubstituted allylic amine derivatives remain
lacking and represent a significant gap in contemporary asym-
metric hydrogenation chemistry. Examples of this type of
transformation mainly involve 1,1-disubstituted derivatives
bearing protecting groups that are not readily removed.3
(2) For the first synthesis, see: (a) Burgey, C. S.; Paone, D. V.; Shaw,
A. W.; Deng, J. Z.; Nguyen, D. N.; Potteiger, C. M.; Graham, S. L.; Vacca,
J. P.; Williams, T. M. Org. Lett. 2008, 10, 3235–3238. (b) For an alternate
approach, see: Janey, J. M.; Orella, C. J.; Njolito, E.; Baxter, J. M.; Rosen,
J. D.; Palucki, M.; Sidler, R. R.; Li, W. L.; Kowal, J. J.; Davies, I. W. J.
Org. Chem. 2008, 73, 3212–3217.
10.1021/ol101804e  2010 American Chemical Society
Published on Web 08/24/2010

From the outset of this program we focused on control of
the olefin geometry as an important element to enable success
of the asymmetric hydrogenation. A high-yielding synthesis
of the geometrically pure diene was developed (Scheme 2),
and our screening began to gauge the reactivity profile of
this unique substrate.4
Table 1. Catalyst Screening for the Asymmetric Hydrogenation
of Diene 2a
Scheme 2. Synthesis of Caprolactam 1
entry metalb ligand
solvent
S/Cc 2:3:4d er 1S:1Re er 4S:4Re
1
2
3
4
5
6
7
8
9
Ir
5
6
7
8
9
DCM
5
1
3
3
3
3
3
3
3
85:11:4
Rh
Ru
Ru
Ru
Ru
Ru
Ru
Ru
MeOH
0:65:35 >99:1
0:30:70 54:46
0:0:100 82:18
52:48
90:10
95:5
EtOH/DCMf
EtOH/DCMf
EtOH/DCMf
0:6:94
0:91:9
0:0:100 74:26
0:63:37 59:41
0:0:100 87:13
52:48
37:63
99:1
10 EtOH/DCMf
11 EtOH/DCMf
12 EtOH/DCMf
13 EtOH/DCMf
>99:1
97:3
86:14
<1:99
a See Supporting Information for experimental details. See Figure 1 for
ligand structures. b Ir and Ru catalysts prepared in situ from chiral phosphine
and (COD)2IrBF4 or (COD)Ru(methallyl)2/HBF4, respectively. Rh catalysts
screened as isolated (ligand)Rh(COD)BF4 complexes. c Substrate/catalyst
ratio. d Determined by chiral HPLC. e Enantiomeric ratio at specified chiral
center in product 4. f 3:2 ratio, respectively.
symmetric biaryl phosphines such as BINAP also gave mod-
erate to high enantioselectivity at the benzylic carbon (Table
1, entries 6-9), although only electron-rich variants such as
Xyl-BINAP (entry 7) and TMBTP (entry 9) showed useful
activity toward the tandem reduction. Interestingly, absolute
selectivity at the amino ester center (C1 in Table 1) was low to
moderate across all the diverse cationic ruthenium catalysts tested.
Further optimization revealed that the cationic ruthenium
catalyst derived from (-)-TMBTP gave the best combination
of reactivity and selectivity, giving full conversion to 4 in 20 h
using only 0.3 mol % catalyst at 65 °C and 70 psig H2 in MeOH
at multikilogram scale. Under these conditions the enantiomeric
ratio at the benzylic stereocenter was 99.6:0.4, while the amino
ester stereocenter was nearly racemic (55:45).6 The hydrogena-
tion of the allylic amine operates under catalyst control, as the
same sense of induction at the benzylic center is obtained
regardless of the configuration of the amino ester center.7 Our
efforts to control the geometry of the allylic amine were justified,
since exposure of a Z-olefin derivative to the optimized reaction
conditions afforded lower enantiomeric ratios (87:13).8
Table 1 shows representative results of initial catalyst screens
employing diene 2. Typical cationic rhodium and iridium
phosphine complexes (Table 1, entries 1 and 2) had insufficient
reactivity to hydrogenate the allylic amine portion of the diene.
Since literature reports indicate that cationic ruthenium systems
display good reactivity with hindered olefins including those
with poorly chelating functional groups,5 we focused on a
diverse library of catalysts generated in situ from chiral
phosphines, (COD)Ru(methallyl)2, and HBF4. Cationic ruthe-
nium catalysts with electron-rich ligands such as Et-DuPHOS
(entry 3) or various Josiphos derivatives (entries 4 and 5) gave
markedly higher reactivity with good to excellent enantiose-
lectivity at the benzylic center. Catalysts derived from C2-
(3) (a) Shultz, S. C.; Krska, S. K. Acc. Chem. Res. 2007, 12, 1320–
1326. (b) Wang, C.-J.; Sun, X.; Zhang, X. Angew. Chem., Int. Ed. 2005,
44, 4933–4935. (c) Deng, J.; Duan, Z.-C.; Huang, J.-D.; Hu, X.-P.; Wang,
D.-Y.; Yu, S.-B.; Xu, X.-F.; Zheng, Z. Org. Lett. 2007, 9, 4825–4828. (d)
Yamano, T.; Yamashita, M.; Adachi, M.; Tanaka, M.; Matsumoto, K.;
Kawada, M.; Uchikawa, O.; Fukatsu, K.; Ohkawa, S. Tetrahedron:
Asymmetry 2006, 17, 184–190. (e) Fahrang, R.; Sinou, D. Bull. Soc. Chim.
Belg. 1989, 98, 387–393. (f) Saylik, D.; Campi, E. M.; Donohue, A. C.;
Jackson, W. R.; Robinson, A. J. Tetrahedron: Asymmetry 2001, 12, 657–
667. (g) Sun, X.; Zhou, L.; Li, W.; Zhang, X. J. Org. Chem. 2007, 72,
1002–1005. (h) Limanto, J.; Shultz, C. S.; Dorner, B.; Desmond, R. A.;
Devine, P. N.; Krska, S. W. J. Org. Chem. 2008, 73, 1639–1642. (i) Brown,
J. M.; Parker, D. J. Org. Chem. 1982, 47, 2722–2725. (j) Broene, R. D.;
Buchwald, S. L. J. Am. Chem. Soc. 1993, 115, 12569–12570. (k) Yamashita,
M.; Yamano, T. Chem. Lett. 2009, 38, 100–101. (l) Burk, M. A.; Allen,
J. G.; Kiesman, W. F. J. Am. Chem. Soc. 1998, 120, 657–663.
Advancing from hydrogenation product 4, a straightforward
process was developed to azapanone 1 involving deprotection,
trifluoroethylation, and cyclization (Scheme 2).9 The trans
relationship between C1 and C4 was effectively established Via
thermodynamic epimerization of the amine center catalyzed by
5 mol % of 2-hydroxy-5-nitrobenzaldehyde in the presence of
Et3N,10 and the synthesis of telcagepant was successfully
completed by coupling with the pyridine heterocycle.2
(6) Benincori, T.; Cesarotti, E.; Piccolo, O.; Sannicol, F. J. Org. Chem.
2000, 65, 2043–2047.
(4) For unsaturated ester preparation, see: (b) Baxter, J. M.; Steinhuebel,
D. P.; Palucki, M.; Davies, I. W. Org. Lett. 2005, 7, 215–218.
(7) Both enantiomers of (Me-DuPHOS)Rh(COD)BF4 were used to
prepare enantiomerically enriched samples of (R)- and (S)-3, which were
then hydrogenated with (COD)Ru(methallyl)2/HBF4/(-)-TMBTP to afford
4 with identical enantioselectivity at the benzylic center.
(5) (a) Genet, J.-P. Acc. Chem. Res. 2003, 36, 908–918, and references
therein. (b) Dobbs, D. A.; Vanhessche, K. P. M.; Brazi, E.; Rautenstrauch,
V.; Lenoir, J.-V.; Genet, J.-P.; Wiles, J.; Bergens, S. H. Angew. Chem.,
Int. Ed. 2000, 39, 11, 1992–1995. (c) Tang, W.; Wu, S.; Zhang, X. J. Am.
Chem. Soc. 2003, 125, 9570.
(8) The monoreduced bis-Boc derivative was used. For similar results
see: (a) Cui, X.; Burgess, K. Chem. ReV. 2005, 105, 3272–3296.
(9) See Supporting Information for experimental details.
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Org. Lett., Vol. 12, No. 18, 2010

Table 2. Scope of Asymmetric Hydrogenation of Allylic Aminesa
entry
olefin
R1
R2
R3
ligand
erb
1
2
3
4
5
6
7
8
9
14
14
14
15
16
17
18
19
20
21
H
H
H
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
10
11
95:5
96:4
90:10
94:6
97:3
96:4
92:8
95:5
91:9
96:4
(-)-13
(-)-13
(-)-13
(-)-13
(-)-13
(-)-13
(-)-13
(-)-13
p-i-PrO-C6H4
p-CF3-C6H4
Me
Ph
Ph
Bn
CH2C(CO2Et)2NHAc
H
CH2C(CO2Et)2NHAc
CH2C(CO2Et)2NHAc
H
10
a S/C ) 50 for most reactions, see Supporting Information for experimental details. b Determined by chiral SFC.
Given the success of the asymmetric hydrogenation of
diene 2, we continued to define the scope with respect to
variously substituted allylic amines. For this purpose, 1,1-
disubstituted olefin 14 was screened against a similar set of
catalysts as in Table 1. With this less hindered substrate,
Rh, Ir, and Ru (neutral and cationic) catalysts all displayed
good reactivity, although only cationic ruthenium catalysts
with C2-symmetric biaryl phosphine ligands gave high levels
of enantioselectivity (Table 2, entries 1-3).11
CD3OD gives deuterium incorporation into the methyl,
methylene, and benzylic positions.13
The results shown in Table 2 illustrate the effect of olefin
substitution on the reaction. Substrates with a 2,3-diaryl
substitution give enantiomeric ratios of >94:6 or higher
(entries 4-6). An alkyl substituent in the 2-position is also
tolerated (entry 7). Substrate 19 (entry 8), structurally related
to 3, also provided good enantioselectivity, while hydrogena-
tion of the corresponding Z-isomer afforded lower selectivity
(entry 9). Lastly, a branched alkyl substituent at C2 was also
a functional substrate (entry 10).
Figure 1. Chiral ligands used in optimization.
A mechanistic investigation of this reaction using olefin
14 revealed that the N-Ac allylic amine is converted to
the enamide upon exposure to the cationic ruthenium
complex in the absence of H2.12 Subsequent hydrogenation
of the isolated enamide under standard reaction conditions
exhibited lower selectivity (71:29). Taken together these
observations suggest that under the standard reaction
conditions olefin isomerization is competitive with hy-
drogenation, and the allylic amine isomer enables higher
enantioselectivity compared with the enamide. Consistent
with this hypothesis is the observation that the hydrogena-
tion of 14 under a D2 atmosphere in either CH3OH or
In summary, we have described a novel, asymmetric hydro-
genation of allylic amines employing commercially available
reagents. We have clearly exemplified the practical utility in
the synthesis of the caprolactam of a contemporary active
pharmaceutical ingredient. We expect widespread utilization of
this novel method in academic and industrial laboratories that
exploit innovative asymmetric hydrogenation methodologies.
Acknowledgment. The authors thank P. Rizos, M. Biba,
Z. Pirzada, T. Brkovic of Process Research for chiral analysis
and R. Reamer of Process Research for NMR analysis.
Supporting Information Available: Experimental pro-
cedures, compound characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) A 96:4 ratio of trans:cis diastereomers was obtained after heating
at 55 °C. For use of salicylaldehyde derivatives in epimerization, see: (a)
Reider, P. J.; Davis, P.; Hughes, D. L.; Grabowski, E. J. J. J. Org. Chem.
1987, 52, 955–957. (b) Armstrong, J. D.; Eng, K. K.; Keller, J. L.; Purick,
R. M.; Hartner, F. W.; Choi, W. B.; Askin, D.; Volante, R. P. Tetrahedron
Lett. 1994, 35, 3239–3242.
OL101804E
(11) Although the N-Boc analogue of 14 also performs in the reaction,
the acetamide-protected gives higher reactivity and selectivity.
(12) The olefin geometry was confirmed by NOE studies.
(13) Under these conditions the enantiomeric ratio decreases from 96:4
to 83:17, consistent with a kinetic isotope effect favoring olefin isomerization
over catalyst turnover via reductive elimination.
Org. Lett., Vol. 12, No. 18, 2010
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