Synthesis of a chiral key intermediate of neurokinin antagonist SSR 240600 by asymmetric allylic alkylation

Article abstract of DOI:10.1055/s-0031-1289878

The preparation of optically active morpholine-2-aryl-2-acetaldehyde from morpholine-2-aryl-3-one is reported. The quaternary carbon is introduced during a palladium-promoted asymmetric allylic alkylation. This is a useful intermediate in the synthesis an

Full text of DOI:10.1055/s-0031-1289878

LETTER
2939
Synthesis of a Chiral Key Intermediate of Neurokinin Antagonist SSR 240600
by Asymmetric Allylic Alkylation
Synthesis
é
of
a
Chiral
r
K
ey Inte
ô
rmediate of
Neurokinin
A
ntagon
e
ist SSR 240600 Keldenich,a,c Christophe Michon,a,b,c Audrey Nowicki,a,c Francine Agbossou-Niedercorn*a,b,c
a
Université Lille Nord de France, 59000 Lille, France
Fax +33(3)20436585; E-mail: francine.agbossou@ensc-lille.fr
b
c
CNRS, UCCS UMR 8181, 59655 Villeneuve d’Ascq, France
ENSCL, CCM-CCCF, Bât C7, BP 90108, 59652 Villeneuve d’Ascq, France
Received 25 August 2011
CF3
Abstract: The preparation of optically active morpholine-2-aryl-2-
acetaldehyde from morpholine-2-aryl-3-one is reported. The qua-
ternary carbon is introduced during a palladium-promoted asym-
metric allylic alkylation. This is a useful intermediate in the
synthesis and development of potent NK antagonist.
F3C
O
NH2
N
N
Key words: alkylation, palladium, asymmetric catalysis, hetero-
O
O
cycle
Cl
The neurokinins (also known as tachykinins) are a peptide
family of neurotransmitters comprising substance P (SP),
neurokinin A (NKA), and neurokinin B (NKB) that share
the common carboxy-terminal sequence Phe-X-Gly-Leu-
Met-NH2. They are widely distributed in the central and
peripheral nervous systems.1 Based on the affinity of nat-
ural neurokinins, three distinct 7-transmembrane G pro-
tein-coupled receptor types have been identified: NK1
(SP-preferring), NK2 (NKA-preferring), NK3 (NKB-pre-
ferring).2 The various forms of neurokinin in the mamma-
lian body affect a large number of biological activities,
including muscle contraction and relaxation, vasodilata-
tion, secretion, activation of the immune system, pain
transmission, and neurogenic inflammation. Thus, antag-
onists of these NK receptors have attracted a great deal of
interest as potent therapeutic agents.3
Cl
N
O
N
SSR 240600
N
O
O
N
Cl
Cl
SSR 241586
Figure 1 Two examples of morpholine-based NK antagonists
OH
Cl
Sharpless
dihydroxylation
Cl
Cl
HO
Cl
TBSO
TBSO
A
H
N
H
Cl
Cl
N
O
crystallization
Amongst optically active morpholines, SSR 240600 and
SSR 241586 have been described to be active against de-
pression, emesis, irritable bowel syndrome, schizophre-
nia, and urinary trouble (Figure 1).4
Cl
Cl
O
OH
OH
B
To implement the stereogenic center of optically active
2,2-disubstituted morpholines,5 several methodologies
have been applied. The first reported methodology relies
on a Sharpless dihydroxylation providing intermediate
A.6 A crystallization of an arylmorpholine carried out in
the presence of D-(–)-tartaric acid furnished the building
block B.7 Then, an asymmetric cyanosilylation allowing
an access to compound C,8 an enantioselective epoxyda-
tion of a homoallylic alcohol providing synthon D,9 and,
very recently, an organocatalyzed Henri reaction deliver-
ing E10 have been reported successively (Scheme 1).
Cl
O
NC
TMSO
Cl
Cl
silylcyanation
epoxidation
TBSO
Cl
TBSO
C
Cl
Cl
Cl
O
Cl
HO
HO
D
E
Cl
O2N
Cl
Henri
reaction
O
EtO
HO
Cl
Cl
EtO2C
O
SYNLETT 2011, No. 20, pp 2939–2942
x
x
.x
x
.2
0
1
1
Advanced online publication: 11.11.2011
DOI: 10.1055/s-0031-1289878; Art ID: B16511ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Different routes to access the benzylic sterocenter of
arylmorpholine precursors

2940
J. Keldenich et al.
LETTER
Following our interest in the use of asymmetric allylic
alkylation in order to prepare quaternary stereocenters,11
and our interest in the preparation of intermediates for the
synthesis of potent NK antagonist,12,13 we considered the
preparation of a key intermediate of SSR 240600 based on
such a methodology.
EtOH, 0 °C,
1h; r.t., 2 h;
reflux, 1 h
EtO
O
OEt
O
O
O
N
+
HO
NHCH2Ph
MgBr
Ph
61%
O
IV
O
N
O
The synthesis of SSR 240600 was meant from the optical-
ly active aldehyde I which would be the result of an oxi-
dative cleavage of the olefin and a reduction of chiral
morpholinone II. The latter would result from an asym-
metric allylation of III. This morpholinone could be ob-
tained easily from morpholinedione IV prepared from 2-
(benzylamino)ethanol (Scheme 2). We focused thus on
the preparation of optically active I.
Cl
Ph
MeI
HO
Cl
THF, 50 °C, 2 h
THF, reflux, 5 h
65%
89%
Cl
Cl
1
O
N
O
O
N
O
TES, TiCl4
Ph
CH2Cl2, –78 °C,
0.5 h
MeO
Ph
H
72%
CF3
Cl
Cl
Cl
F3C
Cl
III
2
O
N
OHC
Scheme 3 Synthesis of the alkylation substrate III
Ph
NH2
O
N
N
O
O
butane] ligand and allylpalladium chloride dimer
(Scheme 4). Results are reported Table 1.
Cl
Cl
I
Cl
Among the various bases tried, the best catalytic condi-
tions were found by using a combination of n-BuLi and
TMEDA (Table 1, entry 7) in conjunction with the palla-
dium complex. Hence, the combined use of THF and a bi-
dentate ligand like TMEDA proved to be crucial breaking
down n-BuLi aggregates to form monomers and dimers
and thereby increasing significantly their basicity.16
Asymmetric allylic alkylation of III was then studied in
the presence of a chiral Trost ligand (Figure 2) and al-
lylpalladium chloride dimer (Table 2). The highest optical
purity was obtained with DACH-naphthyl Trost ligand
(Table 2, entry 3, 83% ee).
Cl
SSR 240600
O
N
O
N
O
Ph
Ph
O
O
N
O
Ph
O
IV
Cl
Cl
III
Cl
Cl
II
HO
NHCH2Ph
Scheme 2 Retrosynthetic analysis of SSR 240600
O
N
O
O
N
O
[Pd(η3-C3H5)Cl]2
(1 mol%)
DPPB (2.2 mol%)
OAc
Morpholinedione IV was easily prepared from 2-(benzyl-
amino)ethanol.14 Thus, the reaction of commercially
available 2-(benzylamino)ethanol (1 equiv) and diethyl-
oxalate (1 equiv) led to IV in 61% yield after purification.
The reaction of IV with freshly prepared (3,4-dichlo-
rophenyl)magnesium bromide (1.1 equiv) afforded the
cyclic hemiketal 1 in 65% yield. Then, 1 was reacted with
methyliodide (1.5 equiv) in the presence of NaH (1.5
equiv).15 After workup, the cyclic ketal 2 was isolated in
89% yield. Then, a Lewis acid promoted silane reduction
of ketal 2 furnished morpholinone III. Thus, ketal 2 was
reacted with TES (3 equiv) in the presence of TiCl4 (6
equiv) in dichloromethane providing morpholinone III in
72% yield (Scheme 3).15 The preparation of III could also
be achieved in one step from 1 under similar conditions (3
h, –78 °C, 73%).
Ph
Ph
H
+
base
additive
THF
Cl
Cl
Cl
II
Cl
III
Scheme 4 Alkylation of the prochiral morpholinone by palladium-
promoted reaction
The absolute configuration of II could be determined by
X-ray structure determination (Figure 3).17 The allyl de-
rivative II obtained from the (R,R)-DACH-naphthyl
ligand has an R-configuration similar to the C2 quaternary
carbon center of the morpholine heterocycle in SSR
240600.
We next reduced compound II with lithium aluminium
hydride. The morpholine 4 was isolated in 70% yield. The
allyl moiety was next oxidized in a two-step procedure us-
ing first N-methylmorpholine-N-oxide along with a cata-
lytic amount of osmium tetroxide, second using sodium
In order to find the most appropriate conditions for the
palladium-catalyzed allylic alkylation of III, we first car-
ried out experiments to screen different bases with the use
of the diphosphine DPPB [1,4-bis(diphenylphosphino-
Synlett 2011, No. 20, 2939–2942 © Thieme Stuttgart · New York

LETTER
Synthesis of a Chiral Key Intermediate of Neurokinin Antagonist SSR 240600
2941
O
O
NH HN
PPh2 Ph2P
(R,R)-DACH-phenyl Trost ligand
O
O
NH HN
PPh2 Ph2P
(R,R)-DACH-naphthyl Trost ligand
PPh2
Ph2P
Figure 3 ORTEP view of compound II with ellipsoids drawn at
O
50% probability level16
O
HN
NH
O
N
O
O
N
Ph
Ph
LiAIH4 (2,5 equiv),
THF, reflux, 2 h
(R,R)-Anden-phenyl Trost ligand
70%
Figure 2 Chiral Trost ligands
Cl
Cl
Cl
Cl
II
4
Table 1 Variation of the Base and Additives in the Alkylation of
IIIa
1. NMO (3 equiv), OsO4 (1 mol%),
THF–H2O (1:1), r.t., 12 h
2. NaIO4 (2 equiv), acetone–H2O
(3:1), r.t., 4 h
O
N
OHC
Ph
Entry
Base (equiv)
LDA (1.5)
LiHMDS (1.5)
(–)-sparteine
NaH
Additive (equiv)
Yield (%)
1
2
3
4
5
6
7b
–
68
49
0
90%
Cl
–
Cl
I
–
Scheme 5 Synthesis of chiral aldehyde I
–
6
s-BuLi (2)
s-BuLi (2)
n-BuLi (1.5)
–
0
periodate. After workup, the aldehyde I was isolated in
90% yield (Scheme 5).
ZnCl2 (1.3)
TMEDA (1)
27
95
In summary, we have developed an efficient route to opti-
cally enriched morpholine-2-aryl-acetaldehyde, a key in-
termediate of potent neurokinin antagonists, exhibiting a
quaternary carbon center. To access the desired R config-
uration of such a quaternary carbon center, the palladium-
catalyzed asymmetric allylic alkylation proved to be a
powerful methodology. Further investigations are under
way to apply this methodology to the preparation of pipe-
ridines bearing also a quaternary carbon center.13
a Reactions were carried out in the presence of [Pd(h3-C3H5)Cl]2 (1
mol%), DPPB (2.2 mol%) in THF at r.t. for 4 h.
b Addition of the base at –78 °C; the reaction was carried out at r.t. for
12 h.
Table 2 Asymmetric Allylation of IIIa
Entry Ligand
Yield (%) ee (%)
1
2
3
4
(R,R)-BINAP
95
93
90
83
46
64
83
16
In a first Schlenk tube under nitrogen, the substrate (1 equiv) was
dissolved in dry THF and cooled to –78 °C. After addition of
TMEDA (1 equiv) and n-BuLi (1.5 equiv), the resulting mixture
was stirred for 30 min at –78 °C. In a second Schlenk tube, [Pd(al-
lyl)Cl]2 (0.01 equiv) and the desired ligand (0.021 equiv) were dis-
solved in dry THF (2 mL). After addition of allyl acetate (1.5
equiv), the mixture was stirred 30 min at r.t. and then cooled to
–78 °C. The solution containing the catalyst was slowly added by
cannula to the substrate solution. The resulting mixture was then al-
lowed to warm up to r.t. overnight (12 h). The reaction was
quenched by the addition of a sat. aq NH4Cl solution (5 mL) and of
H2O (5 mL). The allyl product was extracted with Et2O, and the or-
ganic phases were washed with a sat. NaHCO3 solution. After dry-
(R,R)-DACH-phenyl Trost ligand
(R,R)-DACH-naphthyl Trost ligand
(R,R)-Anden-phenyl Trost ligand
a Reactions were carried out in the presence of [Pd(h3-C3H5)Cl]2 (1
mol%), chiral ligand (2.2 mol%) in THF (0.15 M). The addition of the
base and TMEDA was done at –78 °C, and reaction was carried out
at r.t. for 12 h.
Synlett 2011, No. 20, 2939–2942 © Thieme Stuttgart · New York

2942
J. Keldenich et al.
LETTER
ing over MgSO4 and filtration on silica wool, the solvents were
evaporated under vacuum. The resulting product was further puri-
fied by flash chromatography on silica gel using a solvent mixture
of PE–EtOAc–Et3N (90:5:5). Evaporation of solvents afforded a
colorless oil.
References and Notes
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Compound II
20
1
[a]D –32 (CH2Cl2, c 2.8 mM, for 83% ee). H NMR (300 MHz,
CDCl3): d = 7.81 (d, 1 H, J = 2.0 Hz), 7.58 (dd, 1 H, J = 8.5, 2.3 Hz),
7.43 (d, 1 H, J = 8.1 Hz), 7.29 (m, 5 H), 5.78 (m, 1 H), 5.10 (m, 2
H), 4.68 (d, 1 H, J = 14.6 Hz), 4.62 (d, 1 H, J = 14.3 Hz), 3.85 (m,
1 H), 3.70 (dt, J = 11.1, 3.3 Hz), 3.54 (dt, J = 11.7, 4.6 Hz), 3.03 (m,
1 H), 2.94 (dd, 1 H, J = 7.2 Hz), 2.59 (dd, 1 H, J = 6.8 Hz). 13C
NMR (75 MHz, CDCl3): d = 168.1 (CO), 141.3 (CArC, CIV), 136.3
(CArC, CIV), 132.7 (CArCl, CIV), 132.6 (CAll, CIII), 132.0 (CArCl, CIV),
130.4 (CAr, CIII), 128.9 (CAr, CIII), 128.5 (CAr, CIII), 128.3 (CAr, CIII),
127.9 (CAr, CIII), 126.0 (CAr, CIII), 119.3 (CAll, CII), 83.1 (CAll, CIV),
59.7 (CBn, CII), 50.4 (CH2, CII), 46.6 (CAll, CII), 46.4 (CH2, CII). IR
(KBr): 3075, 3029, 2924, 1653, 1484, 1465, 1190, 1030, 995, 920,
825, 786, 727 cm–1. ESI-HRMS: m/z calcd for C20H20O2NCl2
[MH+]: 376.0870; found: 376.0870. HPLC [DAICEL CHIRAL-
PAK OJ-H, hexane–i-PrOH (9:1), 0.3 mL/min, 200 nm]: tR (major,
R enantiomer) = 41.4 min; tR (minor, S enantiomer) = 49.4 min.
(5) Wijtmans, R.; Vink, M. K. S.; Schoemaker, H. E.; van Delft,
F. L.; Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis 2004, 641.
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Tetrahedron: Asymmetry 1998, 9, 3251.
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1785.
(8) Takamura, M.; Yabu, K.; Nishi, T.; Yanagisawa, H.; Kanai,
M.; Shibasaki, M. Synlett 2003, 353.
Compound III
1H NMR (300 MHz, CDCl3): d = 7.57 (d, 1 H, J = 2.2 Hz), 7.40 (d,
1 H, J = 8.4 Hz), 7.31 (m, 4 H), 7.23 (m, 2 H), 5.15 (s, 1 H), 4.65 (d,
1 H, J = 14.5 Hz), 4.53 (d, 1 H, J = 14.5 Hz), 3.95 (dt, 1 H, J = 4.4
Hz), 3.82 (m, 1 H), 3.45 (m, 1 H), 3.24 (dt, 1 H, J = 3.9 Hz). 13C
NMR (75 MHz, CDCl3): d = 166.8 (CO), 137.6 (CArC, CIV), 136.1
(CArC, CIV), 132.6 (CArCl, CIV), 132.5 (CArCl, CIV), 130.4 (CAr, CIII),
129.7 (CAr, CIII), 129.0 (CAr, CIII), 128.4 (CAr, CIII), 128.0 (CAr, CIII),
127.3 (CAr, CIII), 78.3 (CH, CIII), 62.3 (CBn, CII), 50.2 (CH2, CII),
46.0 (CH2, CII). IR (KBr): 3094, 3025, 2988, 2960, 2921, 1684,
1653, 1484, 1472, 1448, 1199, 1030, 802, 749, 728 cm–1. ESI-
HRMS: m/z calcd for C17H16O2NCl2 [MH+]: 336.05526; found:
336.05510.
(9) Okachi, T.; Murai, N.; Onaka, M. Org. Lett. 2003, 5, 85.
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Gomez-Pardo, D.; Cossy, J. J. Org. Chem. 2011, 76, 2594.
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Angew. Chem. Int Ed. 2011, 50, 3548. (b) Guerrero Rios, I.;
Rosas-Hernandez, A.; Martin, E. Molecules 2011, 16, 970.
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132, 15534. (d) Trost, B. M.; Schroeder, G. M.; Kristensen,
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manuscript in preparation.
(14) Drefahl, G.; Hartmann, M.; Skurk, A. Chem. Ber. 1966,
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Compound I
[a]D20 +102 (CH2Cl2, c 11.0 mM, for 83% ee). 1H NMR (300 MHz,
CDCl3): d = 9.62 (t, 1 H, J = 3.0 Hz), 7.43 (dd, 2 H, J = 5.7, 5.3 Hz),
7.33 (m, 5 H), 7.17 (dd, 1 H, J = 8.4, 2.4 Hz), 3.85 (m, 1 H), 3.75
(m, 1 H), 3.59 (d, 1 H, J = 13.1 Hz), 3.42 (d, 1 H, J = 13.1 Hz), 3.04
(dd, 1 H, J = 15.7, 3.1 Hz), 2.83 (d, 1 H, J = 12.6 Hz), 2.63 (dd, 1
H, J = 15.5, 2.3 Hz), 2.54 (t, 1 H, J = 4.9 Hz), 2.48 (d, 1 H, J = 11.7
Hz). 13C NMR (75 MHz, CDCl3): d = 200.7 (CO), 142.8 (CArC,
CIV), 137.4 (CArC, CIV), 132.9 (CArCl, CIV), 131.7 (CArCl, CIV),
130.6 (CAr, CIII), 129.2 (2 CAr, CIII), 128.7 (CAr, CIII), 128.6 (2 CAr,
CIII), 127.7 (CAr, CIII), 125.7 (CAr, CIII), 75.9 (C, CIV), 63.1 (CH2,
CII), 62.2 (CH2, CII), 59.8 (CH2, CII), 53.5 (CH2, CII), 52.2 (CH2,
CII). IR (KBr): 3028, 2965, 2873, 2766, 1722, 1469, 1461, 1138,
818, 791, 747 cm–1. ESI-MS: m/z 320.0597 [MH+ – CH2CHO],
364.0859 [MH+], 396.1117 [MH+ + CH3OH]. ESI-HRMS: m/z cal-
cd for C19H20O2NCl2 [MH+]: 364.08656; found: 364.08585.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
(17) X-ray crystal data of compound II were deposited under
reference CCDC 836129. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre:
www.ccdc.cam.ac.uk/data_request/cif.
We are grateful to Sanofi-Aventis with Prof. B. Castro and Dr. G.
Ricci for supporting this work (PhD fellowships to J.K. and A.N.).
Support from CNRS is also greatly appreciated. Dr. P. Roussel and
Dr. F. Capet are thanked for the X-ray diffraction analysis. Mrs. N.
Duhal (CUMA, Pharm. Dept., Univ. Lille Nord de France) is
thanked for the mass analysis.
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