Enantioselective synthesis of BMS-204352 (MaxiPost) using N-fluoroammonium salts of cinchona alkaloids (F-CA-BF4).

Article abstract of DOI:10.1039/b303113f

The enantioselective synthesis of a potent Maxi-K potassium channel opener (BMS-204352) mediated by N-fluoroammonium salts of cinchona alkaloids is described. Two synthetic pathways were evaluated. An ee as high as 88% was achieved (>99% after a single re

Full text of DOI:10.1039/b303113f

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Enantioselective synthesis of BMS-204352 (MaxiPost) using
N-fluoroammonium salts of cinchona alkaloids (F–CA–BF4)
Ludivine Zoute, Christophe Audouard, Jean-Christophe Plaquevent and Dominique Cahard*
UMR 6014 de l’IRCOF (Institut de Recherche en Chimie Organique Fine), Université de
Rouen, F-76821 Mont Saint Aignan Cedex, France. E-mail: dominique.cahard@univ-rouen.fr
Received 24th March 2003, Accepted 29th April 2003
First published as an Advance Article on the web 2nd May 2003
The enantioselective synthesis of a potent Maxi-K potas-
sium channel opener (BMS-204352) mediated by N-fluoro-
ammonium salts of cinchona alkaloids is described. Two
synthetic pathways were evaluated. An ee as high as 88%
was achieved (>99% after a single recrystallisation).
3-Fluorooxindoles were identified as potent modulators of
the large-conductance calcium-activated potassium (Maxi-K)
channels and, therefore, are useful in the protection of neuronal
cells, especially in the treatment or prevention of ischemic
stroke. Among several compounds prepared at Bristol-Myers
Squibb laboratories, BMS-204352 (Fig. 1) was found to be a
potent opener of Maxi-K channels.1
Scheme 1 Enantioselective synthesis of 1. Reagents and conditions: (i)
Boc2O, 80 ЊC; (ii) s-BuLi, THF, Ϫ78 ЊC then diethyl oxalate; (iii) 3 M
HCl reflux; (iv) NaH, THF then 2-methoxy-5-chlorophenylmagnesium
bromide, THF, Ϫ20 ЊC to rt; (v) Et3SiH, TFA, 110 ЊC; (vi) F–CA–BF4,
DABCO, THF–CH3CN–CH2Cl2 (1:3:4), Ϫ78 ЊC; (vii) LiHMDS, THF,
Ϫ10 ЊC then F–CA–BF4; (viii) Na2S2O4 then HCl.
Fig. 1 Structure of (S)-(ϩ)-BMS-204352, MaxiPost, 1.
The racemic fluorooxindoles were prepared in a straight-
forward manner. The stereocontrol of the fluorinated carbon
center was obtained by asymmetric hydroxylation using the
appropriate chiral camphorsulfonyl oxaziridine followed by
reaction with diethylaminosulfur trifluoride (DAST).1c An
alternative method to get enantiomerically pure fluorooxin-
doles required a separation by preparative chiral HPLC or a
resolution of an intermediate through the formation of a pair
of diastereomeric salts with (S)-(Ϫ)-α-methylbenzylamine.2 We
considered that an elegant synthetic route would involve late
asymmetric electrophilic fluorination of the prochiral enolate
precursor. For this reason we decided to exploit our new family
of enantioselective fluorinating agents: the N-fluoroammonium
salts of cinchona alkaloids.3 Here, we report a new enantio-
selective synthesis of BMS-204352 with the aid of these chiral
electrophilic fluorinating agents.4
Two routes were evaluated as depicted in Scheme 1.† The key
step in route A is the enantioselective fluorination of the oxin-
dole 4 whereas in route B the stereogenic fluorinated carbon
center is created by enantioselective fluorination at the benzylic
position of the acyclic intermediate arising from condensation
between 5 and 6. Route A utilises the reaction of ortho-
lithiated, protected 3-trifluoromethylaniline with diethyl oxal-
ate, followed by hydrolytic deprotection of the amino moiety
and cyclisation to provide the isatin 3.5 Isatin 3 was converted to
the hydroxy indolone by addition of a Grignard reagent and
then dehydroxylated with triethylsilane and trifluoroacetic acid
to end up with the key intermediate 4 (Scheme 1).1c Next, we
submitted compound 4 to enantioselective electrophilic fluorin-
ation with various cinchona alkaloid [N–F]ϩ salts. In route B,
ester 6 was deprotonated with a first equivalent of lithium bis-
(trimethylsilyl)amide, and reacted in an aromatic nucleophilic
substitution with the fluoroaromatic 5. The resulting product
reacted in situ with a second equivalent of base and the benzylic
anion was fluorinated with a cinchona alkaloid [N–F]ϩ salt.
Reduction of the nitro group in 7 with sodium hydrosulfite and
cyclisation in acidic conditions led to the target molecule 1.6
In previous work, we demonstrated that quinine and quin-
idine-based [N–F]ϩ agents were superior to the two other
cinchona alkaloids: cinchonine and cinchonidine.3c For the
present study, we also noticed that [QN–F]ϩ and [QD–F]ϩ salts
induce a higher degree of enantioselection. Moreover, protec-
tion of the hydroxy group in the [N–F]ϩ reagent was crucial
to achieve high enantioselectivity. Therefore Table 1 only shows
a selection of the best results obtained with the reagents
depicted in Fig. 2 The nature of the ester group influences
enantioselectivity; the best results have been obtained with
F-2NaphtQN-BF4 (88% ee; Table 1, entry 5). Among com-
mercially available bis-alkaloids which were evaluated in this
study, 1,4-bis(9-O-dihydroquinyl)phthalazine served to produce
F-(DHQN)2PHAL-BF4 which shows the same high level of
enantioselectivity (Table 1, entry 6). Nevertheless, this fluorin-
ating agent was not further considered because of the high cost
of the starting bis-alkaloid. Both enantiomers of BMS-204352
are thus attainable, however the (S) enantiomer has demon-
strated higher biological efficiency.2 The nature of the base was
next examined with DABCO being the most efficient base
for high yield and enantioselectivity. A single recrystallisation
from dichloromethane–hexane afforded enantiomerically pure
crystals of 1.
Phase-transfer conditions were also examined by means of
an achiral fluorinating agent (Selectfluor or N-fluorobenzene-
sulfonimide) in the presence of a chiral phase-transfer catalyst
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 8 3 3 – 1 8 3 4
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Table 1 Enantioselective electrophilic fluorination (route A)
Entry
Chiral [N–F]ϩ agent
Base
Ee (%)a
Yield (%)a
1
2
3
4
5
6
7
8
F-pClBzQN-BF4
F-pClBzQD-BF4
F-2NaphtQN-BF4
F-pClBzQN-BF4
F-2NaphtQN-BF4
F-(DHQN)2PHAL-BF4
F-pClBzQN-BF4
F-2NaphtQN-BF4
Quinuclidine
Quinuclidine
Quinuclidine
DABCO
DABCO
DABCO
66 (S)
66 (R)
84 (S)
57 (S)
88 (S)
88 (S)
84 (S)
81 (S)
>98
>98
>98
>98
>98 (96)
90
Cs2CO3
Cs2CO3
>98
>98
a The ee values were determined by HPLC analysis using a Chiralcel OD-H column (hexane–iPrOH) and the absolute configuration was assigned by
comparison with literature data.2 b HPLC determined yields based on starting material. In brackets are isolated yields.
which time the temperature rose from Ϫ78 to 0 ЊC and then quenched
with 8 mL of water. The aqueous phase was extracted with CH2Cl2. The
organic phase was washed with brine, dried (MgSO4) and rotary
evaporated. A purification by column chromatography (silica gel, 4%
MeOH–CH2Cl2) afforded compound 1 in 96% yield. Ee was determined
by chiral HPLC (Chiracel OD-H column, 10% 2-propanol–hexane, 1
mL minϪ1, λ = 254 nm, retention times: (S)-1: 6.0 min, (R)-1: 7.8 min).
Physical and spectroscopic data are in agreement with ref. 4.
Typical procedure for (5-chloro-2-methoxyphenyl)fluoro(2-nitro-4-
trifluoromethylphenyl)acetic acid methyl ester 7. A solution of lithium
bis(trimethylsilyl)amide 1 M in THF (0.88 mL) was added dropwise to
a mixture of 1-fluoro-2-nitro-4-trifluoromethylbenzene 5 (0.48 mmol,
100.4 mg) and (5-chloro-2-methoxyphenyl)acetic acid methyl ester 6
(0.4 mmol, 85.8 mg) in THF (10 mL) at Ϫ10 ЊC. The mixture was
stirred for 90 min and then cooled to Ϫ40 ЊC for the addition of a
solution of F-2NaphtQN-BF4 (280 mg, 0.48 mmol) in acetonitrile
(5 mL). After stirring overnight, during which time the temperature
rose to 5 ЊC, the mixture was quenched with water (15 mL) and the
aqueous phase was extracted with CH2Cl2. The organic phase was dried
(MgSO4) and rotary evaporated. A purification by column chromato-
graphy (silica gel, cyclohexane–CH2Cl2, 1:1) afforded compound 7 in
88% yield. IR (CHCl3) ν 1766, 1720, 1542, 1326, 1260, 1133, 830, 719
cmϪ1; 1H NMR (CDCl3, 300 MHz) δ 3.72 (s, 3H), 3.96 (s, 3H), 6.96 (d,
Fig. 2 Selected structures of N-fluoroammonium salts of cinchona
J = 8.7 Hz, 1H), 7.20 (m, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.47 (m, 1H),
7.78 (m, 1H), 8.06 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 54.0, 56.7, 95.5
(d, J = 193 Hz), 114.1, 122.3 (d, J = 3.5 Hz), 122.9 (q, J = 272 Hz), 126.5,
126.7, 128.5 (q, J = 3.5 Hz), 129.5 (d, J = 8 Hz), 131.3 (d, J = 4.6 Hz),
132.1, 132.8 (d, J = 35 Hz), 135.2 (d, J = 23 Hz), 148.9, 156.2 (d, J =
3 Hz), 168.3 (d, J = 25 Hz); 19F NMR (CDCl3, 282 MHz) δ Ϫ63.48 (3F),
alkaloids.
derived from cinchona alkaloids (for example O(9)-allyl-N-9-
anthracenylmethylcinchonidinium bromide).7 Unfortunately,
the enantioselection never exceeded 13%, however the conver-
sion into 1 was total.
20
Ϫ142.989 (1F); [α]D = Ϫ8.25 (c 0.4, CH2Cl2). Ee was determined by
chiral HPLC (Chiralpak AS column, 15% 2-propanol–heptane, 0.5 mL
minϪ1, λ = 254 nm, retention times: (S)-7: 13.3 min, (R)-7: 15.0 min).
In an alternative route to 1, acyclic α-fluoroester 7 was
targeted (route B, Scheme 1). Various bases (t-BuOM, NaH,
LiHMDS and KHMDS) and fluorinating agents (same as in
route A) were examined. We demonstrated that LiHMDS is the
base of choice for the SNAr and the fluorination of the ester
enolate is best achieved with F-2NaphtQN-BF4. Nevertheless
the best enantiomeric excess recorded did not exceeded 36%.
Interestingly, a single recrystallisation of 7 from cyclohexane
afforded enantiomerically pure compound (>99% ee). Upon
reduction of the nitro group in 7 with sodium hydrosulfite,
the anilino-ester spontaneously cyclised to provide enantio-
merically pure 1.
In summary, we have developed an efficient enantioselective
synthesis of the potent maxi-K channel opener BMS-204352
with the aid of N-fluoroammonium salts of cinchona alkaloids.
Among the diverse routes explored, fluorination of the oxin-
dole 4 allowed the efficient synthesis of BMS-204352 in up to
88% ee, and >99% ee after a single recrystallisation.
1 (a) V. K. Gribkoff, J. E. Starrett, Jr, S. I. Dworetzky, P. Hewawasam,
C. G. Boissard, D. A. Cook, S. W. Frantz, K. Heman, J. R. Hibbard,
K. Huston, G. Johnson, B. S. Krishnan, G. G. Kinney, L. A.
Lombardo, N. A. Meanwell, P. Molinoff, R. A. Myers, S. L. Moon,
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Notes and references
† Typical procedure for 3-(5-chloro-2-methoxyphenyl)-3-fluoro-6-tri-
fluoromethyl-1,3-dihydroindol-2-one 1. To
a solution of 1,4-diaza-
bicyclo[2.2.2]octane (35 mg, 0.31 mmol) in THF (1 mL) was added 3-
(5-chloro-2-methoxyphenyl)-6-trifluoromethyl-1,3-dihydroindol-2-one
4 (48 mg, 0.14 mmol) at 20 ЊC. The mixture was stirred for 30 min,
then the temperature was cooled to Ϫ78 ЊC. N-Fluoro-2-naphthoyl-
quininium tetrafluoroborate (F-2NaphtQN-BF4) (99.4 mg, 0.17 mmol)
was dissolved in a mixture of 3 mL CH3CN–4 mL CH2Cl2 and added
over a period of one hour. The mixture was stirred overnight during
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 8 3 3 – 1 8 3 4
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