Efficient enantioselective formal synthesis of Ro 67-8867, a NMDA 2B receptor antagonist

Article abstract of DOI:10.1055/s-2005-865225

An efficient enantioselective formal synthesis of Ro 67-8867 has been achieved in 7 steps using an amino-zinc-ene-enolate cyclization and an enantioselective ring enlargement of a substituted prolinol as the key steps.

Full text of DOI:10.1055/s-2005-865225

1170
LETTER
Efficient Enantioselective Formal Synthesis of Ro 67-8867, a NMDA 2B
Receptor Antagonist
S
ynthesi
n
s
of Ro 67-88
g
67,
a
N
MD
A
r
2B Re
i
ceptor
A
d
ntagonist Déchamps,a Domingo Gomez Pardo,a Phillipe Karoyan,b Janine Cossy*a
a
Laboratoire de Chimie Organique associé au CNRS, Ecole Supérieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI),
10 rue Vauquelin, 75231 Paris Cedex 05, France
b
UMR, CNRS 7613, Structure et Fonction de Molécules Bioactives, Université Paris VI, case 45, 4 place Jussieu, 75252 Paris Cedex 05,
France
Fax +33(1)40794660; E-mail: janine.cossy@espci.fr
Received 2 February 2005
Ph
Ph
Ph
(+)-O,O'-
bibenzoyl-
D-tartaric acid
Abstract: An efficient enantioselective formal synthesis of Ro 67-
8867 has been achieved in 7 steps using an amino-zinc-ene-enolate
cyclization and an enantioselective ring enlargement of a substitut-
ed prolinol as the key steps.
OH
OH
O
H2/ C*cat
N
N
N
t-BuOK,
i-PrOH
Ph
rac-A
Ph
(S,S)-A
Ph
rac-B
Key words: amino-zinc-ene-enolate cyclization, asymmetric syn-
thesis, ring expansion, piperidines, prolinol
i-Pr
i-Pr
H
N
H
H
Cl
Ru
Cl
P
P
MeO
MeO
Ph
Ro 67-8867 is a high affinity, selective, and activity-de-
pendent antagonist of the N-methyl-D-aspartate (NMDA)
receptor. NMDA receptor subtypes with different phar-
macological properties are formed by heteromeric assem-
bly of different subunits. It is proposed that by selectively
blocking a NMDA receptor subtype in brain regions vul-
nerable to ischemic damage, neuroprotection will be
achieved without the unwanted side effects of non-selec-
tive NMDA receptor antagonist1 (Figure 1).
N
H
Ph
C*=
i-Pr
i-Pr
Scheme 1 Enantioselective synthesis of piperidin-3-ol (S,S)-A
The precursor for the amino-zinc-ene-enolate cyclization,
the unsaturated amine 3, was synthesized in two steps
from (R)-phenylethylamine (1). (R)-phenylethylamine (1)
was treated with 1-bromobut-3-ene in the presence of
K2CO3 and NaI (DMF, 100 °C) to afford the secondary
amine 2 in 79% yield.3c The alkylation of amine 2 with
ethyl 2-bromoethanoate in the presence of K2CO3 (DMF,
r.t.) led to the desired amino ester 3 in 79% yield.3c This
later compound was converted in a one-pot procedure to
the 3-benzyl derivative 5.5 After deprotonation with LDA
in THF at –78 °C, the lithium enolate of aminoester 3 was
transmetalated with zinc bromide (3 equiv, 1 M in Et2O).
The solution was warmed up to room temperature and af-
ter cyclization, the organozinc intermediate 4 was trans-
metalated with the active Pd(II) complex, obtained by
oxidative addition of the aryl iodide to the Pd(0) complex
generated in situ from Pd2dba3 and tri-o-tolylphosphine.
The coupling reaction was achieved at room
temperature3h to give 5 in 43% yield with an excellent dia-
stereoselectivity as the cis-isomer was the only detectable
compound.6 In order to transform prolinol 6 to piperidin-
3-ol 7, by applying a ring expansion, pyrrolidinoester 5
was reduced to prolinol 67 using LiAlH4 (THF, r.t.,
yield = 95%). In agreement with previous results on the
ring expansion of substituted prolinols,8 compound 6 was
treated with trifluoroacetic anhydride (TFAA) in THF,
then with triethylamine, followed by the addition of
NaOH and, under these conditions, 3-hydroxypiperidine
79 was the only isolated product in 70% yield and with a
diastereomeric excess superior to 95%. The hydrogenoly-
sis of piperidine 7 over Pd/C in EtOH allowed the isola-
tion of the desired 3-hydroxypiperidine 810 in 94% yield.
HO
N
S
OH
O
O
Figure 1 Ro 67-8867
The first synthesis of Ro 67-8867 has been achieved from
ethyl 4-bromobutyrate in 9 steps.2 This synthesis involved
an optical resolution of a racemic substituted piperidin-3-
ol rac-A with (+)-O,O¢-dibenzoyl-D-tartaric acid, but the
yield of the desired optically active piperidin-3-ol (S,S)-A
was only 10–12% after 4 to 5 crystallizations. However,
the enantioselective hydrogenation of piperidinone rac-B
under dynamic-kinetic resolution conditions was success-
ful, by using [RuCl2(diphosphine)(chiral diamine)] C*, as
(S,S)-A was obtained with a good enantiomeric excess
(97%)2d (Scheme 1).
Here, we would like to report a short and enantioselective
access to Ro 67-8867 by utilizing a diastereoselective and
enantioselective amino-zinc-ene-enolate cyclization3 and
an enantioselective ring expansion of optically active pro-
linols.4
SYNLETT 2005, No. 7, pp 1170–1172
0
2.
0
5.
2
0
0
5
Advanced online publication: 14.04.2005
DOI: 10.1055/s-2005-865225; Art ID: G04305ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Ro 67-8867, a NMDA 2B Receptor Antagonist
1171
NH2
Br
COOEt
K2CO3
CH2=CH(CH2)2Br
K2CO3, NaI
N
COOEt
NH
DMF, r.t.
79%
DMF, 100 °C
79%
1
2
3
1. LDA, THF, −78 °C
2. ZnBr2
Ph
Ph
COOEt
ZnBr
Pd2dba3
P(o-tolyl)3, PhI
LiAlH4
CH2OH
N
N
COOEt
N
THF
95%
43%
6
5
4
1. TFAA, THF
2. Et3N
3. NaOH
70%
Ph
THF
O
O
S
OH
Ph
H2
Cl
OH
Pd/C (10%)
N
OH
9
HO
N
ref.2d
(85%)
EtOH
94%
N
H
S
O
Ph
O
7
8
OH
(dr > 95%)
Ro 67-8867
Scheme 2 Enantioselective formal synthesis of Ro 67-8867
Marek, I.; Normant, J. J. Org. Chem. 1998, 63, 2442.
The obtention of compound 8 represents a formal synthe-
sis of Ro 67-8867 as its transformation to Ro 67-8867 was
achieved in one step by treatment with sulfone 92d
(Scheme 2).
(e) Karoyan, P.; Chassaing, G. Tetrahedron Lett. 2002, 43,
253. (f) Karoyan, P.; Chassaing, G. Tetrahedron Lett. 2002,
43, 1221. (g) Karoyan, P.; Quancard, J.; Vaissermann, J.;
Chassaing, G. J. Org. Chem. 2003, 68, 2256. (h) Quancard,
J.; Magellan, H.; Lavielle, S.; Chassaing, G.; Karoyan, P.
Tetrahedron Lett. 2004, 45, 2185. (i) Quancard, J.;
Labonne, A.; Jacquot, Y.; Chassaing, G.; Lavielle, S.;
Karoyan, P. J. Org. Chem. 2004, 69, 7940.
Ro 67-8867 can be obtained in 7 steps with an overall
yield of 11%.
(4) For comprehensive reviews, see: (a) Cossy, J.; Gomez
Pardo, D. Chemtracts 2002, 15, 579. (b) Cossy, J.; Gomez
Pardo, D. Targets in Heterocyclic Systems 2002, 6, 1.
(5) Analytical Data.
Acknowledgment
Johnson & Johnson is greatly acknowledged for financial support
(Focus Giving Program to J. Cossy).
Compound 5: [a]D20 +39.2 (c 1.4, CHCl3). IR (neat): 2962,
1724, 1491, 1450, 1371, 1160, 1089, 1026, 769, 740, 706
cm–1. 1H NMR: d = 7.23–7.02 (m, 10 H), 4.06 (m, 2 H), 3.64
(q, J = 6.8 Hz, 1 H), 3.36 (d, J = 7.9 Hz, 1 H), 2.97 (dt,
J = 8.3, 3.4 Hz, 1 H), 2.80–2.69 (m, 2 H), 2.54 (m, 1 H), 2.23
(dd, J = 13.2, 10.6 Hz, 1 H), 1.75–1.61 (m, 2 H), 1.29 (d,
J = 6.8 Hz, 3 H), 1.15 (t, J = 7.2 Hz, 3 H). 13C NMR:
d = 173.4 (s), 144.5 (s), 140.5 (s), 128.6 (d), 128.3 (d), 128.2
(d), 127.5 (d), 127.1 (d), 126.0 (d), 66.7 (d), 61.8 (d), 59.9 (t),
50.2 (t), 43.7 (d), 37.1 (t), 29.7 (t), 22.7 (q), 14.3 (q). MS
(EI): m/z (relative intensity) = 337 (1) [M+], 265 (23), 264
(100), 143 (4), 106 (5), 105 (56), 104 (3), 103 (6), 91 (19),
79 (7), 77 (6), 68 (5).
References
(1) (a) Grauert, M.; Bechtel, W. D.; Ensinger, H. A.; Merz, H.;
Carter, A. J. J. Med. Chem. 1997, 40, 2922.
(b) Guzikowski, A. P.; Whittemore, E. R.; Woodward, R.
M.; Weber, E.; Keana, J. F. W. J. Med. Chem. 1997, 40,
2424. (c) Gee, K. R.; Niu, L.; Schaper, K.; Jayaraman, V.;
Hess, G. Biochemistry 1999, 38, 3140.
(2) (a) Alanine, A.; Burner, S.; Buettelmann, B.; Heitz Neidhart,
M.-P.; Jaeschke, G.; Pinard, E.; Wyler, R. WO 0075109,
2000; Chem. Abstr. 2000, 134, 42064. (b) Crameri, Y.;
Scalone, M.; Waldmeier, P.; Widmer, U. EP 1136475, 2001;
Chem. Abstr. 2001, 135, 272882. (c) Alanine, A.;
Buettelmann, B.; Fisher, H.; Huwyler, J.; Heitz Neidhart,
M.-P.; Jaeschke, G.; Pinard, E.; Wyler, R. WO 0216321,
2002; Chem. Abstr. 2002, 136, 216649. (d) Scalone, M.;
Waldmeier, P. Org. Process Res. Dev. 2003, 7, 418.
(3) (a) Karoyan, P.; Chassaing, G. Tetrahedron Lett. 1997, 38,
85. (b) Lorthiois, E.; Marek, I.; Normant, J. Tetrahedron
Lett. 1997, 38, 89. (c) Karoyan, P.; Chassaing, G.
(6) Compound 5 was the only product detected by 1H NMR and
GC-MS.
(7) Analytical Data.
Compound 6: [a]D20 +8.6 (c 4.3, CHCl3). IR (neat): 3420,
3015, 2920, 1600, 1485, 1445, 1370, 1310, 1155, 1080,
1025, 765, 745, 705, 700 cm–1. 1H NMR: d = 7.28–7.14 (m,
7 H), 7.13–7.05 (m, 3 H), 3.72 (q, J = 6.8 Hz, 1 H), 3.54 (dd,
J = 10.9, 3.02 Hz, 1 H), 3.46 (dd, J = 11.1, 4.1 Hz, 1 H), 3.04
(m, 1 H), 2.86–2.73 (m, 2 H), 2.60 (m, 1 H), 2.32–2.15 (m,
2 H), 1.54–1.40 (m, 2 H), 1.36 (d, J = 6.8 Hz, 3 H).
Tetrahedron: Asymmetry 1997, 8, 2025. (d) Lorthiois, E.;
Synlett 2005, No. 7, 1170–1172 © Thieme Stuttgart · New York

1172
I. Déchamps et al.
LETTER
13C NMR: d = 143.5 (s), 141.2 (s), 128.6 (d), 128.4 (d),
128.4 (d), 127.7 (d), 127.2 (d), 125.9 (d), 62.6 (d), 62.2 (d),
60.4 (t), 50.8 (t), 43.1 (d), 36.2 (t), 31.3 (t), 22.3 (q). MS (EI):
m/z (relative intensity): 295 (1) [M+], 280 (5), 265 (22), 264
(100), 161 (8), 160 (66), 143 (6), 106 (8), 105 (79), 103(8),
91 (27), 79 (10), 77 (9), 68 (7).
(9) Analytical Data.
Compound 7: [a]D20 –24.6 (c 1.1, CHCl3). IR (neat): 3492,
3009, 2910, 2798, 1600, 1491, 1451, 1395, 1210, 1095,
1060, 762, 709 cm–1. 1H NMR: d = 7.27–7.13 (m, 7 H),
7.12–7.05 (m, 3 H), 3.55–3.40 (m, 2 H), 2.99 (m, 1 H), 2.90–
2.80 (m, 1 H), 2.76–2.64 (m, 2 H), 2.45 (dd, J = 13.2, 6.4 Hz,
1 H), 1.98 (m, 1 H), 1.80 (m, 1 H), 1.54–1.31 (m, 3 H), 1.28
(d, J = 6.8 Hz, 3 H). 13C NMR: d = 143.0 (s), 140.8 (s), 129.2
(d), 128.3 (d), 128.2 (d), 127.6 (d), 127.1 (d), 125.7 (d), 66.7
(d), 63.6 (d), 56.5 (t), 50.6 (t), 42.6 (d), 38.8 (t), 26.9 (t), 18.4
(q). MS (EI): m/z (relative intensity) = 295 (11) [M+], 281
(23), 280 (100), 218 (14), 190 (6), 105 (32), 103 (4), 91 (18),
79 (5), 77 (5).
(8) (a) Cossy, J.; Dumas, C.; Michel, P.; Gomez Pardo, D.
Tetrahedron Lett. 1995, 36, 549. (b) Cossy, J.; Dumas, C.;
Gomez Pardo, D. Synlett 1997, 905. (c) Cossy, J.; Dumas,
C.; Gomez Pardo, D. Bioorg. Med. Chem. Lett. 1997, 7,
1343. (d) Wilken, J.; Kossenjans, M.; Saak, W.; Haase, D.;
Pohl, S.; Martens, J. Liebigs Ann. 1997, 573. (e) Langlois,
N.; Calvez, O. Synth. Commun. 1998, 28, 4471. (f) Davis,
P. W.; Osgood, S. A.; Hébert, N.; Sprankle, K. G.; Swayze,
E. E. Biotechnol. Bioeng. 1999, 61, 143. (g) Cossy, J.;
Dumas, C.; Gomez Pardo, D. Eur. J. Org. Chem. 1999,
1693. (h) Michel, P.; Rassat, A. J. Org. Chem. 2000, 65,
2572. (i) Cossy, J.; Mirguet, O.; Gomez Pardo, D. Synlett
2001, 1575. (j) Brandi, A.; Cicchi, S.; Paschetta, V.; Gomez
Pardo, D.; Cossy, J. Tetrahedron Lett. 2002, 43, 9357.
(k) Deyine, A.; Delcroix, J.-M.; Langlois, N. Heterocycles
2004, 64, 207.
(10) Analytical Data.
Compound 8: [a]D20 –36.6 (c 1, CHCl3). IR (neat): 3290,
2915, 1604, 1532, 1452, 1282, 1263, 1110, 1001, 848, 753,
706 cm–1. 1H NMR: d = 7.24–7.07 (m, 5 H), 3.52–3.46 (m,
1 H), 2.99–2.86 (m, 2 H), 2.68 (d, J = 13.6, 7.5 Hz, 1 H),
2.58–2.47 (m, 5 H), 1.65–1.27 (m, 3 H). 13C NMR: d = 140.6
(s), 129.2 (d), 128.2 (d), 125.8 (d), 66.3 (d), 53.1 (t), 46.5 (t),
42.6 (d), 39.3 (t), 27.2 (t). MS (EI): m/z (relative intensity) =
191 (100) [M+], 162 (9), 147 (8), 131 (7), 118 (32), 115 (13),
100 (20), 92 (11), 91 (67), 82 (22), 77 (11), 72 (11), 71 (42),
Synlett 2005, No. 7, 1170–1172 © Thieme Stuttgart · New York