A chiral synthesis of (-)-spiro[1-azabicyclo[2.2.2]octane-3,5′- oxazolidin-2′-one]: A conformationally restricted analogue of acetylcholine that is a potent and selective α7 nicotinic receptor agonist

Article abstract of DOI:10.1021/jo049404q

A direct, short chiral synthesis of the selective α7 nicotinic receptor agonist (-)-spiro[1-azabicyclo[2.2.2]-octane-3,5′-oxazolidin- 2′-one] (AR-R17779) is presented. The key step utilized attack of the dianion of the (R)-HYTRA ester [(R)-(+)-2-hydroxy-1,2,2-triphenylethyl acetate] on quinuclidin-3-one, followed by a selective precipitation of the diasteriomeric tertiary alcohol that led to (S)-(-)-AR-R17779 in two additional steps.

Full text of DOI:10.1021/jo049404q

an extremely useful tool for understanding R7 ACh NRs
because to date it is the only potent and selective R7
AChNR agonist available.8 AR-R17779 is a single (-)-
enantiomer, and it is over 100-fold more potent as an R7
AChNR agonist than its (+)-antipode. The original ra-
cemic synthesis6,7 that produced AR-R17779 and its (+)-
enantiomer utilized the reaction of the enolate of tert-
butyl acetate with 3-quinuclidinone (Scheme 1). The
resulting tert-butyl â-hydroxyester was converted to the
corresponding methyl ester [(()-2a ], which was then con-
verted to the hydrazide [(()-3]. The desired racemic cyclic
carbamate [(()-4] was obtained via a Curtius rearrange-
ment [55% of racemate from quinuclidinone (1)]. Resolu-
tion of (()-4 with dibenzoyl-L-tartaric acid afforded AR-
R17779 [(-)-4], but in a very poor yield (6%, 3% overall
yield from 1). Since our original synthesis of AR-R17779
required this low-yielding, classical resolution to obtain
the pure, single (-)-enantiomer of 4 (AR-R17779), we
desired a direct stereogenic synthesis of AR-R17779. This
note details the successful outcome of that effort.
Previous reports on the use of HYTRA ester dianion
enolates suggested that that reagent could attack alde-
hydes in a diastereogenic fashion differentiating between
the faces of the aldehyde carbonyl.9 This property of the
dianion enolate of the HYTRA esters was much less
precedented for prochiral ketones. However, viewing
3-quinuclinone as the appropriate precursor for the
synthesis of AR-R17779, we reacted the dianion enolate
of (R)-HYTRA ester [(R)-5]10 with quinuclidinone (Scheme
2). Not surprisingly, the reaction only provided a modest
diastereoselectivity (approximately 3:2), favoring the
desired (R,S)-diastereomer of 2b. However, serendipi-
tously, the solubility of the two diastereomers in chloro-
form was vastly different. This property was easily
exploited with the desired (R,S)-diastereomer precipitat-
ing upon digestion in chloroform of the crude reaction
solid. After recovering a second crop, the yield of the
desired ester [(R,S)-2] was 48%. Direct conversion of the
ester [(R,S)-2] to the hydrazide [(S)-3]was accomplished
by using hydrazine in methanol with sodium cyanide as
an aminolysis catalyst.11 In this step, transesterification
likely occurred first, liberating the (R)-HYTRA alcohol
and forming the chiral methyl ester. Hydrazinolysis then
followed to form (S)-3. The (R)-HYTRA alcohol was easily
recovered in this step by simple precipitation from water.
The resulting aqueous solution of the hydrazide [(S)-3]
was then directly subjected to a Curtius rearrangement
to afford (S)-(-)-4 [AR-R17779, 37%]. The overall yield
in this synthesis of stereogenically pure (-)-AR-R17779
A Ch ir a l Syn th esis of
(-)-Sp ir o[1-a za bicyclo[2.2.2]octa n e-3,5′-
oxa zolid in -2′-on e]: A Con for m a tion a lly
Restr icted An a logu e of Acetylch olin e Th a t
Is a P oten t a n d Selective r7 Nicotin ic
Recep tor Agon ist
J ohn E. Macor,*,1 George Mullen, Patrick Verhoest,
Anthony Sampognaro, Bruce Shepardson, and
Robert A. Mack2
CNS Discovery, AstraZeneca, 1800 Concord Pike,
Wilmington, Delaware 19850-5437
john.macor@bms.com
Received April 9, 2004
Abstr a ct: A direct, short chiral synthesis of the selective
R7 nicotinic receptor agonist (-)-spiro[1-azabicyclo[2.2.2]-
octane-3,5′-oxazolidin-2′-one] (AR-R17779) is presented. The
key step utilized attack of the dianion of the (R)-HYTRA
ester [(R)-(+)-2-hydroxy-1,2,2-triphenylethyl acetate] on qui-
nuclidin-3-one, followed by a selective precipitation of the
diasteriomeric tertiary alcohol that led to (S)-(-)-AR-R17779
in two additional steps.
The ubiquitous role of acetylcholine (ACh) as a key
neurotransmitter has been well documented.3 In par-
ticular, ACh is the natural agonist for neuronal nicotinic
receptors, whose activation has been linked to important
processes such as modulating neurotransmission and
sensory gating.4 Deficiency of ACh nicotinic activation
has been associated with cognition deficits (including
Alzheimer’s Disease), psychosis, depression, and anxiety.5
Not surprising, there are a multitude of ACh nicotinic
receptors, and crucial to understanding the role of each
of the nicotinic receptors is the discovery of agents that
can selectivity mimic the action of ACh at a single nico-
tinic receptor subtype. To this end, we have recently dis-
closed the discovery of a conformationally restricted ana-
logue of ACh (AR-R17779) which is selective for the R7
nicotinic receptor (R7 AChNR).6,7 AR-R17779 represents
(1) Present address: Bristol-Myers Squibb, Pharmaceutical Re-
search Institute, 5 Research Parkway, Wallingford, CT 06492. Fax:
203-677-7884.
(2) Deceased: This paper is dedicated to the memory of the
outstanding chemist Robert A. Mack.
(3) Decker, M. W.; Brioni, J . D.; Bannon, A. W.; Arneric, S. P.
Diversity of Neuronal Nicotinic Acetylcholine Receptors: Lessons from
Behavior and Implications for CNS Therapeutics. Life Sci. 1995, 56,
545-570.
(4) Holladay, M. W.; Dart, M. J .; Lynch, J . K. Neuronal Nicotinic
Acetylcholine Receptors as Targets for Drug Discovery. J . Med. Chem.
1997, 40, 4169-4194.
(5) Lindstrom, J . Nicotinic Acetylcholine Receptors in Health and
Disease. Mol. Neurobiol. 1997, 15, 193-222.
(8) Recently, a number of patents and patent applications have been
published describing new R7 ACh NRs agonists (and antagonists),
claiming these compounds to be potent and selective agents. However,
to date, only AR-R17779 has been fully described in the peer reviewed
literature.
(6) Mullen, G.; Napier, J .; Balestra, M.; DeCory, T.; Hale, G.; Macor,
J .; Mack, R.; Loch, J ., III; Wu, E.; Kover, A.; Verhoest, P.; Sampagnaro,
A.; Phillips, E.; Zhu, Y.; Murray, R.; Griffith, R.; Blosser, J .; Gurley,
D.; Machulskis, A.; Zongrone, J .; Rosen, A.; Gordon, J . (-)-Spiro[1-
azabicyclo[2.2.2]octane-3,5′-oxazolidin-2-one, a Conformationally Re-
stricted Analogue of Acetylcholine, is a Highly Selective Full Agonist
at the R7 Nicotinic Acetylcholine Receptor. J . Med. Chem. 2000, 43,
4045-4050.
(9) Braun, M.; Graf, S. Stereoselective Aldol Reaction Of Doubly
Deprotonated (R)-(+)-2-Hydroxy-1,2,2-triphenylethyl Acetate (Hytra):
(R)-3-Hydroxy-4-methylpentanoic Acid. Org. Synth. 1998, Collect. Vol.
IX, 497-502.
(10) Macor, J . E.; Sampognaro A. J .; Verhoest, P.; Mack, R. A. (R)-
(+)-2-Hydroxy-1,2,2-triphenylethyl Acetate (1,2-Ethanediol, 1,1,2-tri-
phenyl-, 2-acetate, R-). Org. Synth. 2000, 77, 45.
(11) Hoegberg, T.; Stroem, P.; Ebner, M.; Raemsby, S. Cyanide as
an efficient and mild catalyst in the aminolysis of esters. J . Org. Chem.
1987, 52, 2033-2036.
(7) Gordon, J . C.; Griffith, R. C.; Murray, R. J .; Balestra, M. U.S.
Patent 6,051,581, issued April 18, 2000.
10.1021/jo049404q CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/26/2004
J . Org. Chem. 2004, 69, 6493-6495
6493

SCHEME 1
SCHEME 2
amide in THF (33 mL, 66 mmol) was added dropwise over 55
min to a suspension of (R)-(+)-1,1,2-triphenyl-1,2-ethanediol-2-
acetate10 (10 g, 30 mmol) in 100 mL of THF, with stirring at
-78 °C. The reaction was allowed to warm gradually over 30
min to 0 °C, stirred for an additional 15 min, and then recooled
to -78 °C. To this orange solution was added a solution of
1-azabicyclo[2.2.2]octan-3-one (1, 3.75 g, 30 mmol) in THF (60
mL) dropwise over 35 min. The reaction then was stirred for 2
h, and quenched via addition of a saturated solution of aqueous
NH4Cl (55 mL) over 15 min, followed by the addition of water
(100 mL). The resulting white precipitate was filtered off, rinsed
with water, and dried. This solid was heated in chloroform (150
mL) and the mixture cooled to ambient temperature and filtered
to give 5.7 g of ester [(R,S)-(+)-2]. An additional 0.9 g (total yield
48%) was obtained from the mother liquor by recrystallization:
mp 225-226 °C (CHCl3). HPLC (hydrocarb S 4.6 × 25 mm, 1:1
CH3CN/0.5 M NaClO4, 1.00 mL/min) 9.67 min (98%); [R]22D +91
(c 1.1, DMSO); 13C NMR (200 MHz, DMSO-d6) δ 170.0, 145.1,
144.6, 137.1, 128.7, 127.5, 126.8, 126.7, 126.5, 78.9, 78.4, 69.6,
62.6, 46.1, 45.8, 44.5, 31.4, 23.4, 21.4; 1H NMR (200 MHz,
DMSO-d6) δ 7.61-6.98 (m, 15H), 6.57 (s, 1H), 6.30 (s, 1H), 4.25
(s, 1H), 2.74-2.28 (m, 8H), 1.81 (m, 1H), 1.58-1.20 (m, 3H),
1.20-0.97 (m, 1H); IR (KBr, cm-1) 1715; ESMS m/z 458. Anal.
Calcd for C29H31NO4 + 1.75% CHCl3: C, 74.97; H, 6.72; N, 3.01.
Found: C, 75.01; H, 6.71; N, 2.96.
was 6-fold greater than the original synthesis [18%
versus 3% from quinuclidinone (1), respectively]. Thus,
this enantioselective route provided a very direct and
scaleable access to this key agonist selective for R7 ACh
NRs. This synthetic route also gave easy access to the
inactive (R)-(+)-enantiomer of 4, using the (S)-HYTRA
ester.
In summary, we have used the enolate of (R)-HYTRA
ester [(R)-(5)] to provide a succinct, stereoselective, and
improved route to a key pharmacological tool for studying
R7 ACh NRs (AR-R17779), and this methodology provides
ready access to significant quantities of this tool for
further in vivo evaluations.
Exp er im en ta l Section
Melting points were determined in capillary tubes on an oil
bath apparatus and are uncorrected. Optical rotations were
measured with a digital polarimeter. NMR spectra were deter-
mined in the indicated solvent on a 200- or a 500-MHz NMR
spectrometer at the ambient temperature with tetramethylsilane
(TMS) as the internal standard. Chemical shifts are given in
ppm and coupling constants are in hertz. Splitting patterns are
designated as follows: s, singlet; br s, broad singlet; d, doublet;
t, triplet; q, quartet; m, multiplet. Infrared spectra were recorded
on a FTIR spectrophotometer. Mass spectra were recorded by a
quadrupole mass spectrometer for desorption chemical ionization
(CI) or by a mass spectrometer for electrospray (ES). High-
resolution mass spectra were obtained with a QTOF mass
spectrometer. Elemental analyses were performed internally and
were within 0.4% of the theoretical value when indicated by
symbols of the elements, unless otherwise noted.
(S)-(-)-2′,2′,1′-Tr ip h en yl-2-h yd r oxyeth yl-(R)-3-h yd r oxy-
1-a za bicyclo[2.2.2]octa n e-3-a ceta te [(S,R)-(-)-2b]. Using the
identical conditions described above, reaction of 2.75 g (8.27
mmol) of (S)-(-)-1,1,2-triphenyl-1,2-ethanediol-2-acetate, 940 mg
(7.51 mmol) of 1-azabicyclo[2.2.2]octan-3-one (1), and 10.3 mL
(20.6 mmol) of a 2.0 M solution of lithium diisopropylamide in
THF provided 1.74 g (51%) of the S,R-ester [(S,R)-(-)-2b]: mp,
223-224 °C (CHCl3); [R]22 -88 (c 1.0, DMSO); chiral HPLC
D
(96.5%); 13C NMR (200 MHz, DMSO-d6) δ 170.0, 145.1, 144.6,
137.1, 128.7, 127.5, 126.8, 126.7, 126.5, 78.9, 78.4, 69.6, 62.5,
46.1, 45.8, 44.4, 31.4, 23.4, 21.4; 1H NMR (200 MHz, DMSO-d6)
(R)-(+)-2′,2′,1′-Tr ip h en yl-2-h yd r oxyeth yl-(S)-3-h yd r oxy-
1-a za bicyclo[2.2.2]octa n e-3-a ceta te [(R,S)-(+)-2b]. Under a
nitrogen atmosphere, a 2.0 M solution of lithium diisopropyl-
6494 J . Org. Chem., Vol. 69, No. 19, 2004

δ 7.48 (m, 2H), 7.38-7.00 (m, 13H), 6.58 (s, 1H), 6.03 (s, 1H),
4.28 (s, 1H), 2.70-2.31 (m, 8H), 1.93-1.71 (m, 1H), 1.57-1.00
(m, 4H). Anal. Calcd for C29H31NO4 + 1.74% CHCl3: C, 74.97;
H, 6.72; N, 3.01. Found: C, 74.43; H, 6.78; N, 3.03.
80 °C and stirred for 3 h. The solution was then cooled in an ice
bath, basicified to pH 11 with concentrated NH4OH, saturated
with NaCl, and extracted with CHCl3 (4 × 50 mL). The organic
extract was cooled in an ice bath and treated with HCl gas to
afford the hydrochloride salt of (S)-(-)-4 [(-)-AR-R17779] as a
(S)-(-)-Sp ir o[1-a za b icyclo[2.2.2]oct a n e-3,5′-oxa zolid in -
2′-on e] [(S)-(-)-4, AR-R17779]. Hydrazine (2 mL, 64 mmol) and
KCN (40 mg, 0.61 mmol) were added to a suspension of (R,S)-
(+)-2b (5.66 g, 12.4 mmol) in MeOH (225 mL). The suspension
was then heated to reflux under a nitrogen atmosphere for 24
h, cooled to ambient temperature, and concentrated to a
semisolid in vacuo. The semisolid was heated to reflux in water,
then cooled and filtered. The resulting white solid was recrystal-
lized from methanol to give returned (R)-(+)-1,1,2-triphenyl-1,2-
ethanediol-2-acetate [5, 2.88 g (80%), [R]22D +219 (c 1.0, MeOH)
(lit. value, +220)].
The aqueous filtrate, containing the hydrazide [(S)-3], was
concentrated to 30 mL, cooled in an ice bath, and acidified to
pH 1 with concentrated HCl. A solution of sodium nitrite (880
mg, 12.8 mmol) in water (5 mL) was added dropwise over 15
min (gas evolution), and the resulting solution was heated to
white solid (1.0 g, 37%): [R]22 -63.9 (c 1.0, MeOH) identical in
D
all physical aspects as has been previously reported.6
(R)-(+)-Sp ir o[1-a za bicyclo[2.2.2]octa n e-3,5′-oxa zolid in -
2′-on e] [R-(+)-4]. Reaction of 1.0 g (2.18 mmol) of ester (S,R)-
(-)-2b with 0.34 mL of hydrazine and 7 mg (5 mol %) of KCN
under the above conditions gave hydrazide [(R)-3] along with
returned (S)-1,1,2-triphenyl-ethane-1,2,-diol (500 mg), [R]22
D
-206 (c 1.0, EtOH) (lit. value, -214). Following treatment with
NaNO2 (155 mg, 2.25 mmol), the intermediate hydrazide (R)-3
was converted to [R-(+)-4] and isolated as its HCl salt (150 mg,
31%): [R]22 +63 (c 1.0, MeOH). The other physical properties
D
were identical to its antipode.
J O049404Q
J . Org. Chem, Vol. 69, No. 19, 2004 6495