Enantioselective synthesis of (+)- l -733,060 and (+)-CP-99,994: Application of an ireland-claisen rearrangement/michael addition domino sequence

Article abstract of DOI:10.1055/s-0029-1219200

An efficient asymmetric synthesis of (+)-l-733,060, (-)-(2S,3R)-1 and (+)-CP-99,994, starting from a Baylis-Hillman adduct, is described. The key steps include a novel domino reaction: stereoselective Ireland-Claisen rearrangement, asymmetric Michael addi

Full text of DOI:10.1055/s-0029-1219200

LETTER
387
Enantioselective Synthesis of (+)-L-733,060 and (+)-CP-99,994: Application of
an Ireland–Claisen Rearrangement/Michael Addition Domino Sequence
Enantioselective
S
a
ynthesis of
r
(+)-
L
-73
c
3,060and
(
i
+
)-CP-
s
99,994 o M. Garrido,* Mercedes García, M. Rosa Sánchez, David Díez, Julio G. Urones
Departamento de Química Orgánica, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008 Salamanca, Spain
Fax +34(923)294574; E-mail: nmg@usal.es
Received 12 October 2009
Dedicated with respect and affection to Professor Pelayo Camps García on the occasion of his 65th birthday
dine over long reaction times (otherwise we observed a
Abstract: An efficient asymmetric synthesis of (+)-L-733,060, (–)-
(2S,3R)-1 and (+)-CP-99,994, starting from a Baylis–Hillman ad-
duct, is described. The key steps include a novel domino reaction:
stereoselective Ireland–Claisen rearrangement, asymmetric Micha-
mixture of 4 and 5).11 Compound 4 could also be obtained
from 5 by rearrangement upon treatment with CsF. When
these compounds were treated either separately or as a
el addition, and piperidone ring formation through a one-pot reac- mixture with lithium amide12 (S)-2, we achieved the result
tion hydrogenolysis/lactamization and a stereoselective inversion of
shown in Scheme 2 and Table 1.
a hydroxy group.
Key words: domino reactions, chiral piperidines, asymmetric syn-
thesis, chiral auxiliaries, d-amino acids
CF3
H
N
O
F3C
The non-peptidic neurokinin NK1 receptor antagonists1
(+)-L-733,060 and (+)-CP-99,994 (Figure 1) are known
for having a variety of biological activities, including neu-
rogenic inflammation,2 pain transmission and regulation
of the immune response.3 They have been implicated in a
variety of disorders such as migraine,4 rheumatoid
arthritis5 and pain.6
OMe
Ph
N
H
Ph
N
H
(+)-L-733,060
CF3
(+)-CP-99,994
MeO HN
Ph
O
F3C
The cis-relationship between the two substituents on the
piperidine ring is essential for high-affinity binding to the
human NK1 (hNK1) receptor. Considering their pharma-
cological importance, various methods have been devel-
oped to access compounds (+)-L-733,0607 and (+)-CP-
99,994.8 Compound ( )-1 has been shown to be less active
(IC50 300 nM) than (+)-L-733,060 (IC50 1.0 nM) but the
quinuclidine derivative CP-96,345 is more active (IC50
0.7 nM),1 thus, methodologies that allow structural modi-
fications are of great value.
Recently, we have demonstrated9 a novel domino reaction
involving a stereoselective Ireland–Claisen rearrange-
ment and asymmetric Michael addition. A protocol start-
ing from Baylis–Hillman adducts 4 using chiral lithium
amide (S)-2 affords optically active g-substituted d-ami-
noacids 6 (Scheme 1). The acid can be transformed into
2,3-disubstituted piperidines 7.
N
Ph
N
H
Ph
CP-96,345
(–)-(2S,3R)-1
Figure 1
Ph
R3
R1
COOR2
OAc
Ph
N
R1
COOH
R1
Ph
N
COOR2
(4R,5R)-6
H
Ph
N
Li
4
(2R,3R)-7
(S)-2
Scheme 1
We observed a better yield of d-amino acid 6, from isomer
4, than from 5, by a domino reaction: stereoselective Ire-
land–Claisen rearrangement13 and asymmetric Michael
addition. The reaction proceeded according to the pro-
posed mechanism9 which, in the case of 4, required initial
allylic acetate rearrangement.14 In any event, the acid
could be easily separated by acid–base extraction. Thus,
d-amino acid (+)-6 could be obtained in 60% yield (de
>95%)15 by reaction of acetate 4 with chiral lithium amide
(S)-2 (Table 1, entry 4) using sequential addition of n-
butyllithium in THF at –78 °C to the amine and then add-
ing the acetate in THF, followed by acid extraction and
further crystallization from EtOAc/hexane. It is worth
In order to demonstrate further the versatility of this meth-
odology to access enantiomerically pure piperidine deriv-
atives, the synthesis of (+)-L-733,060, its C-3 epimer (–)-
(2S,3R)-1 and (+)-CP-99,994, were undertaken.
The synthesis of (+)-L-733,060 started from Baylis–
Hillman adduct 3 (Scheme 2).10 Compound 3 provided
the acetyl derivative 4 by treatment with Ac2O and pyri-
SYNLETT 2010, No. 3, pp 0387–0390
1
2.
0
2.
2
0
1
0
Advanced online publication: 19.01.2010
DOI: 10.1055/s-0029-1219200; Art ID: D28909ST
© Georg Thieme Verlag Stuttgart · New York

388
N. M. Garrido et al.
LETTER
Ph
Ph
Ph
Ph
N
Ph
N
OAc
Ph
N
COOMe
COOMe
COOMe
e
Ph
Ph
COOMe
Ph
Ph
PhCHO
+
Table1
OH
N
Ph
N
Ph
c
5
a
55%
(+)-8
COOMe
75%
Ph
Ph
Ph
(–)-9
(+)-10
d
93%
Ph
COOMe
3
b
COOMe
OAc
e
Ph
N
88%
Ph
Table1
COOH
Ph
4
COOMe
(+)-6
Scheme 2 Reagents and conditions: (a) DBU; (b) Ac2O–pyridine; (c) AcCl, Et3N; (d) CsF, PhCH2N+Et3Cl–, THF; (e) (S)-2, n-BuLi.
noting that when isomerization of 5 into 4 was not com- (64% yield in two steps).19 Attempts at direct inversion,
plete, the mixture of acetates 4/5 could still be used with- when (+)-17 was subjected to conventional Mitsunobu
out further purification (Table 1, entry 1), because the reaction20 and several recent modifications,21 were unsuc-
acid 6 is easy to separate from the reaction mixture.
cessful. Consequently, we decided to invert the hydroxy
group of (+)-17 in two steps. Thus, Swern oxidation,22 fol-
lowed by stereoselective reduction23 of (+)-18, using
CeCl3 and NaBH4, gave the desired N-Boc-2,3-cis-
hydroxypiperidine (+)-19 in 72% yield over two steps
from (+)-17.
Table 1 Reactions of 5 and/or 4 with Chiral Lithium Amide (S)-2a
Entry
5
4
(+)-6
(%)
(+)-10
(–)-9
(+)-8
(mmol) (mmol)
(%)b
(%)b
(%)b
1
2
3
4
6 × 10–2 30 × 10–2 50
16
50
9
5
–
3
6
5
–
3
2
Benzylation of the hydroxy group with 3,5-bis(trifluo-
romethyl)benzyl bromide, in the presence of NaH, yielded
(+)-20. Finally, N-Boc deprotection of (+)-20 using TFA
afforded the target molecule (+)-L-733,060 {[a]D26 +32.6
0.5
–
–
22
54
60
1.8
9.2
26
(c 1.06, CHCl3); Lit.24a [a]D +34.3 (c 1.32, CHCl3),
–
14
Lit.24b [a]D25 +36.2 (c 0.66, CHCl3)} in 75% yield.
a The enantiomers of these compounds can be obtained by treatment
Furthermore, this methodology was applied to the syn-
thesis of (+)-CP-99,994 from adduct (+)-18 (Scheme 5).
Addition/elimination of 2-methoxy-benzylamine to the
with (R)-2.
b See Garrido et al.9
In a one-pot reaction, hydrogenolysis of d-amino acid (+)-
6 with 10% Pd/C in AcOH under 50 psi of H2 and subse-
quent lactamization in situ, gave (–)-11 in 73% yield
(Scheme 3). The piperidin-2-one was converted into me-
thyl ketone (–)-13 in two steps via the Weinreb amide16 (–
)-12 [formed with O,N-dimethylhydroxyl amine hydro-
chloride in THF using n-butyllithium as base (98%)], fol-
lowed by addition of MeMgBr17 in THF to furnish methyl
ketone (–)-13 in 83% yield. Baeyer–Villiger oxidation18
of (–)-13 with urea hydrogen peroxide (UHP) in the pres-
ence of TFAA was performed to yield (–)-14. Reduction
of the lactam in (–)-14 was readily accomplished with
LAH in THF, affording a mixture of lactam 15 and amino
alcohol 16 with 19 and 44% yields, respectively. Because
16 was obtained in low yield and lactam reduction was not
complete, we increased the amount of LAH and the period
of reflux, then the crude reduction product was treated
with (Boc)2O to provide (+)-17 in 83% yield.
O
MeO
MeOOC
a
b
N
(+)-6
Me
73%
98%
Ph
N
H
O
Ph
N
H
O
(–)-11
(–)-12
c
83%
O
O
d
O
60%
Ph
N
H
(–)-14
O
Ph
N
O
H
(–)-13
e
f
83%
HO
HO
Ph
HO
Ph
+
Ph
N
N
H
15
O
N
H
16
Boc
(+)-17
The total synthesis of (+)-L-733,060 required inverting the
hydroxy group of (+)-17 (Scheme 4), although direct ac-
cess to the C-3 epimer (–)-(2S,3R)-1 is possible by treat-
ment with 3,5-bis(trifluoromethyl)benzyl bromide, in the
presence of NaH, followed by deprotection with TFA
19%
44%
Scheme 3 Reagents and conditions: (a) H2, Pd/C, AcOH; (b) Me-
ONHMe·HCl, n-BuLi, THF; (c) MeMgBr (3.0 M in THF); (d) UHP,
CH2Cl2, TFAA, Na2HPO4; (e) LAH, THF; (f) (i) LAH, THF; (ii)
Boc2O, THF.
Synlett 2010, No. 3, 387–390 © Thieme Stuttgart · New York

LETTER
Enantioselective Synthesis of (+)-L-733,060 and (+)-CP-99,994
389
CF3
CF3
HO
Ph
O
HO
Ph
a
c
a
d
O
O
65%
78%
72%
92%
F3C
F3C
N
Ph
N
N
Boc
Boc
Boc
Ph
N
Ph
N
(–)-21
(+)-17
(+)-18
(+)-19
(+)-20
Boc
Boc
b
99%
b
75%
CF3
CF3
O
O
F3C
F3C
Ph
(–)-(2S,3R)-1
N
Ph
N
H
H
(+)-L-733,060
Scheme 4 Reagents and conditions: (a) 3,5-bis(trifluoromethyl)benzyl bromide, NaH, DMF; (b) (i) TFA, CH2Cl2; (ii) sat. NaHCO3; (c)
NMO, TPAP; (d) CeCl3, NaBH4.
piperidin-3-one (+)-18 gave the corresponding imine,
which was treated with NaBH3CN to provide (+)-22 in
57% yield. Treatment of (+)-22 with HCl(g) followed by
base treatment, provided (+)-CP-99,99425 {[a]D26 +69.3 (c
Acknowledgment
The authors are grateful to the FSE, Spanish MEC (CTQ2009-
11172/BQU) and Junta de Castilla y León (Spain) for financial sup-
port: (SA001A09) and excellence GR-178. The authors also thank
Dr. A. M. Lithgow for recording the NMR spectra and Dr. César
Raposo for recording the mass spectra. M.R.S.C. thanks the Univer-
sity of Salamanca for an FPI doctoral fellowship.
20
0.60, CHCl3); Lit.8 [a]D +74.2 (c 0.5, CHCl3)} in 70%
yield.
O
H
N
H
N
a
b
References and Notes
57%
70%
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Ph
N
OMe
OMe
Ph
N
Ph
N
Boc
H
Boc
(+)-18
(+)-22
(+)-CP-99,994
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Scheme 5 Reagents and conditions: (a) 2-methoxybenzylamine,
NaBH3CN; (b) (i) HCl(g), MeOH; (ii) sat. NaHCO3.
In summary, a ten-step, asymmetric synthesis of the neu-
rokinin substance P receptor antagonist amino piperidine
(+)-L-733,060 has been developed with an overall yield
from the Baylis–Hillman adduct 6, of 8.6%. Highlights of
the synthesis include an efficient domino reaction, stereo-
selective Ireland–Claisen rearrangement, and asymmetric
Michael addition of acetyl derivative 4 to give the d-ami-
no acid (+)-6 (de >95%, ee >95%). The synthesis of the C-
3 epimer (–)-(2S,3R)-1 was achieved in 9.8% yield in
eight steps from 4, and (+)-CP-99,994 in 5.5% yield in
nine steps. Clearly, the analogous series of reactions de-
ploying the enantiomer of lithium amide (R)-2 in the dom-
ino reaction step will allow simple access to the
enantiomers of the aforementioned compounds. Taking
into account the interesting properties of other surrogate
structures, such as CP-96,345, and because the described
methodology allows for a range of modifications, work is
currently underway in our laboratory to further develop
this approach.
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1:5.
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Synlett 2010, No. 3, 387–390 © Thieme Stuttgart · New York

390
N. M. Garrido et al.
LETTER
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2.72 (td, J = 11.8, 1.8 Hz, 1 H, H-6), 3.09 (d, J = 11.4 Hz,
1 H, H-6), 3.40 (dt, J = 9.8, 4.1 Hz, 1 H, H-3), 3.52 (d,
J = 9.0 Hz, 1 H, H-2), 4.06 (d, J = 12.3 Hz, 1 H, OCHAH),
4.44 (d, J = 12.3 Hz, 1 H, OCHHB), 7.26–7.45 (m, 7 H,
ArH), 7.68 (s, 1 H, ArHFpara). 13C NMR (100 MHz, CDCl3):
d = 24.9 (CH2, C-5), 31.3 (CH2, C-4), 46.6 (CH2, C-6), 67.6
(CH, C-2), 70.0 (CH2, OCH2), 81.3 (CH, C-3), 121.1 (CH,
ArFpara), 121.9 (C, CCF3), 123.2 (C, q, J = 271.0 Hz, CCF3),
124.6 (C, CCF3), 127.2 (2 × CH, ArFortho), 127.9 (3 × CH,
Phortho + para), 128.3 (2 × CH, Phmeta), 131.3 (C, q, J = 33.0 Hz,
CCF3), 141.1 (C, CipsoF), 141.6 (C, Cipso). HRMS (ESI): m/z
[M + H]+ calcd for C20H20ONF6: 404.1449; found: 404.1421.
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could be derived from such a rearrangement in a bis-allylic
ester system.
(15) A diastereomeric excess of 89% was measured by 1H NMR
spectroscopic analysis of the crude product and >95% after
crystallization. With a t-Bu ester of 4 we achieved >95% de
in the crude material (ref. 9). An ee of >95% is consistent
with the high optical purity of the lithium amide used.
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(25) All compounds were fully characterized by a range of
methods including high-resolution mass spectrometry; the
physical and spectroscopic data of reported compounds were
in full agreement with those reported in the literature.
(19) Physical Data of (–)-(2S,3R)-1: [a]D26 –36.0 (c 0.85, CHCl3).
IR (film): 2929, 2857, 1373, 1346, 1278, 1174, 1133, 887,
843, 756, 700 cm–1. 1H NMR (400 MHz, CDCl3): d = 1.46
(dq, J = 12.6, 4.0 Hz, 1 H, H-4), 1.67–1.89 (m, 1 H, H-5),
1.83 (d, J = 13.1 Hz, 1 H, H-5), 2.26–2.35 (m, 1 H, H-4),
Synlett 2010, No. 3, 387–390 © Thieme Stuttgart · New York

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