Efficient preparation of (3S)-3-(4-fluorobenzyl)piperidinium mandelate

Article abstract of DOI:10.1055/s-2004-834903

Methods for the preparation of (3S)-3-(4-fluorobenzyl)piperidine (2) and its mandelate salt (9) are described. The first generation synthesis started from 3-benzylpiperidone, and required Boc protection of the nitrogen for efficient separation of the enantiomers using chromatography on a chiral stationary phase. Subsequently, a resolution method using (R)-mandelic acid, produced high %ee salt 9 after recrystallization and eliminated the need for Boc protection. The third generation route, starting from pyridine-3- carboxaldehyde, led to a streamlined synthesis of racemate 2 and was optimized for producing multi-hundred gram quantities of the chiral salt.

Full text of DOI:10.1055/s-2004-834903

9
2
PAPER
Efficient Preparation of (3S)-3-(4-Fluorobenzyl)piperidinium Mandelate
E
G
fficient
P
reparati
e
on of (3
S
)-3
o
-
(4-Fluorob
r
g
e
ridinium
M
e
andelate C. Emmett, Gary A. Cain, Melissa J. Estrella, Edd R. Holler, James S. Piecara, Andrew M. Blum,
Alfred J. Mical, Christopher A. Teleha, Dean A. Wacker*
Bristol-Myers Squibb Co., Pharmaceutical Research Institute, Discovery Chemistry, PO Box 5400, Princeton, NJ 08542-5400, USA
Fax +1(609)8186570; E-mail: dean.wacker@bms.com
Received 8 June 2004; revised 1 September 2004
As shown in Scheme 1, the initial method started with
Abstract: Methods for the preparation of (3S)-3-(4-fluoroben-
commercially available N-benzyl-3-piperidone hydrate
hydrochloride 3. Since the benzyl group was not compat-
zyl)piperidine (2) and its mandelate salt (9) are described. The first
generation synthesis started from 3-benzylpiperidone, and required
ible with later transformations, we found that the removal
tiomers using chromatography on a chiral stationary phase. Subse- of this functionality was best affected early in the se-
Boc protection of the nitrogen for efficient separation of the enan-
quently, a resolution method using (R)-mandelic acid, produced
high %ee salt 9 after recrystallization and eliminated the need for
quence. Debenzylation provided a product that was prone
to polymerization, necessitating the protection of the pip-
eridine nitrogen with Boc O to afford Boc-protected 4 in
2
Boc protection. The third generation route, starting from pyridine-
3
-carboxaldehyde, led to a streamlined synthesis of racemate 2 and
was optimized for producing multi-hundred gram quantities of the
chiral salt.
7
ported, at this early phase of the project we found that col-
8% yield. Although distillation of 4 was previously re-
5
umn chromatography was equally effective. Wittig
Key words: piperidines, chiral resolution, enantiomeric resolution,
medicinal chemistry
olefination of 4 was accomplished with phosphonium salt
5
by the action of either n-butyllithium or potassium t-but-
oxide in THF which gave 6 as a mixture of olefin isomers
by NMR spectroscopy in 75% and 92% yield, respective-
ly. No attempts were made to separate the 4:3 mixture or
to determine the exact identity of each isomer. Olefin 6
was smoothly hydrogenated by the action of hydrogen and
Substituted benzyl piperidines have been a rich source of
pharmacological activity, and numerous drugs possess
this general core fragment. Although an expeditious syn-
1
thesis of 4-substituted piperidine 1 had been reported, we
were specifically interested in the preparation of isomeric
5
% Pd/C in methanol and provided rac-7 in 95% yield. It
is important to note that throughout this whole sequence,
while the Boc group was in place, no adverse reactivity
problems with the piperidine nitrogen were seen. The
chiral separation of rac-7 on Chiralcel OJ HPLC column,
using a mixture of butyl chloride and hexane, provided the
chiral Boc-piperidines 7(S) and 7(R) in excellent recovery
2
-substituted piperidine 2, a compound which lacks the
3
symmetrical substitution of piperidine 1. Additionally, we
wished to develop robust chemistry, investigating the lab-
oratory scale preparation of semi-bulk (multi-hundred
gram) quantities of 2.
6
and %ee. Deprotection with 4 N HCl in dioxane provided
F
free piperidine 2 in 79% yield. It should be noted that 2
had some instability in the free base form; as such, it was
best stored in the protected Boc form until needed.
H
Although the route in Scheme 1 was effective for the rapid
preparation of low-end hundred gram quantities of chiral
piperdines 2, we were intrigued at the idea of developing
an alternative method that was more amenable to scale-
up. A major concern was the requirement of chiral HPLC
for separation of the enantiomers. Clearly a process that
made use of a diastereomeric crystallization would be far
more attractive in a scale-up setting. Therefore, we
screened a short list of chiral acids for their effectiveness
to form a salt with piperidine rac-2 (Scheme 2). Our
search quickly narrowed to (R)-2-phenylpropionic acid
and (R)-mandelic acid, but only mandelic acid formed a
solid 8a when mixed in equimolar proportions with rac-2.
The mandelate product 8a was insoluble in diethyl ether
at high concentration, and rendered a solid in 81% yield.
No characterization of 8a was preformed at this point. We
were quite fortuitous to find acetonitrile was a good sol-
vent for recrystallization of 8a. Although the mass recov-
ery (53%) was not optimal at this screening phase, we
N
N
F
H
H
1
2
Figure 1 Piperidine compounds of interest
At the onset of this investigation, not much was known
about the preparation of 3-benzylpiperidines. A route to 3-
substituted piperidines by radical cyclization of menthol
derivatives was also described; however, this was not
viewed as workable on the scales we required. A patent
described the diastereomeric salt of a related unsubstitut-
ed benzylpiperidine, but the preparation was not detailed
3
4
nor were experimental conditions provided.
SYNTHESIS 2005, No. 1, pp 0092–0096
x
x
.
x
x
.2
0
0
4
Advanced online publication: 02.11.2004
DOI: 10.1055/s-2004-834903; Art ID: M04304SS
Georg Thieme Verlag Stuttgart · New York
©

PAPER
Efficient Preparation of (3S)-3-(4-Fluorobenzyl)piperidinium Mandelate
93
+
5
ClPh3 P
OH
OH
HCl
O
1
) H2, Pd/C MeOH
F
KOtBu, THF
2%
2) Boc2O, THF
N
N
aq NaHCO3
9
tBuO
O
Ph
99%
3
4
H
H
O
H2, Pd/C
EtOH
1) HCl, dioxane
2) aqueous base
9%
N
F
N
F
N
F
H
95%
tBuO
O
tBuO
7
H
H
H
H
6
rac-7
rac-2
2 (S)
Chirocel OJ
7
(S)
H
H
7
(R)
2 (R)
Scheme 1
were very encouraged to see that the free-base of salt 9 materials for the synthesis. Both were commercially avail-
showed a non-zero optical rotation ([a] +5.0, EtOH). able and inexpensive without the benefit of bulk pricing at
D
Since a method for the direct measurement of% enrich- this early stage of research. As shown in Scheme 3, the
ment of 2 was not available, the free-base of 9 was treated Grignard reaction between 10 and 11 occurred in diethyl
with Boc O/aqueous bicarbonate in THF and provided en- ether at –5 °C and provided 12 in good yield. For ease of
2
riched 7(S). Use of the chiral HPLC method (Chiralcel OJ purification, the HCl salt 12a was prepared using 4 N HCl
column) showed that the enrichment was 78% in favor of in dioxane in an overall 78% yield of the product. The
the desired enantiomer 7(S). These results suggested that conversion of 12 to rac-2 required two different reduction
pursuing a scale-up method that relied on a diastereomeric reactions: pyridine to piperidine reduction, and the reduc-
resolution with (R)-mandelic acid was going to be fruitful. tion of the secondary hydroxyl to a methylene group. Sev-
This crystallization method had the added benefit of pro- eral attempts were made to conduct these reductions
viding a synthetically useful salt form of 2(S); use of 7(S) simultaneously using hydrogen gas as the reducing agent,
entailed deprotection and free-basing before use. Opera- via the catalysis of either palladium- or platinum-based re-
tionally speaking, use of the salt 9 was viewed as more agents. Although some of the desired rac-2 could be de-
convenient than the Boc-protected material and this fu- tected, we found that competing reduction of the F-phenyl
eled our pursuit of this route.
group made this streamlined approach not viable. We
therefore pursued a sequential reduction protocol, investi-
gating the C–O bond reduction first. We recently reported
the use of in situ generated iodotrimethylsilane as an effi-
cacious reagent for reducing benzylic alcohols. We were
gratified to find this reagent worked well and provided the
7
benzylpyridine 13 in 99% yield. However, we quickly re-
The next phase of our research was to develop a scalable
method for preparation of rac-2. Based on a strategy that
provides the complete carbon framework for the target,
we explored the use of pyridine-3-carboxaldehyde (10)
and 4-fluorophenyl magnesium bromide (11) as starting
7
H
H
H
4
N HCl
HX
dioxane
Et O
2
N
F
N
H
F
N
H
F
HX
Boc
rac-2
8a HX = (R)-mandelic acid
8
rac-7
b HX = (S)-2-Ph-propionic acid
H
H
1
) free base
OH
recryst. from
CH3CN
8a
2
) Boc2O, THF
aq NaHCO3
Ph
CO2-
N
H2
F
N
F
Boc
7
(S) (78% ee)
9
Scheme 2
Synthesis 2005, No. 1, 92–96 © Thieme Stuttgart · New York

9
4
G. C. Emmett et al.
PAPER
1)
BrMg
11
OH
F
TMSCl
NaI
Et O, – 5 oC
CHO
2
[H2]
X
rac-2
2) HCl, dioxane
MeCN
N
+
N
HCl
F
N
F
10
1
3
1
1
2 free base
2a HCl salt
OH
TMSCl
NaI
H
(R)-mandelic
acid
PtO2, H2
EtOH
12a
9
MeCN
MeCN
N
H
F
N
H
F
14
rac-2
Scheme 3
alized our progress towards hydrogenation of the pyridine tection/deprotection steps. Our results and methods have
3 met with the same deleterious side reactions noted ear- been used to prepare up to 630 g of salt 9 without incident
1
lier. Ultimately, we were able to obtain rac-2 by reversing and excellent reproducibility. Further details of this tech-
the order of the reduction sequence. Hydrogenation of the nology will be published elsewhere.
pyridine ring of 12a, using 5% platinum oxide in ethanol,
first provided 14, which was further reduced with TMSI
to provide rac-2. It should be noted that in this two-step
Melting points were determined on an Electrothermal melting point
apparatus and are uncorrected. NMR spectra were recorded at 300
protocol, there were appreciable amounts of 2 detected in MHz using a Varian VXR400 in CDCl (referenced to TMS) unless
the hydrogenation, thus complicating the characterization otherwise noted. Mass spectral data were obtained on either VG 70-
3
VSE (FAB, high-resolution FAB, high resolution DCI) or Finnigan
MAT 8230 (DCI) mass spectrometers. Combustion analyses were
and yield determination of 14. However, this product mix
converged to product rac-2 after treatment with TMSI.
performed by Quantitative Technologies, Inc., Bound Brook, NJ.
The conditions for these reactions were robust enough to
allow this through-process for conversion of 12 to 2 with-
Solvents and reagents were used as purchased from commercial
suppliers unless otherwise indicated. 4-Fluorobenzyltriphenylphos-
out purification. One additional optimization that we
found during our investigation was the preparation of HCl out purification.
phonium chloride (5) was purchased from Avocado and used with-
salt 12a, which alleviated the need for column purification
early in the sequence. Additionally, the acid served to aid
tert-Butyl 3-(4-Fluorobenzyl)piperidine-1-carboxylate (rac-7)
To a solution of 1-benzyl-3-piperidone (102.6 g, 0.41 mol) in
in the conversion of the pyridine to piperidine 14. We had
MeOH (1.4 L) was carefully added 10% palladium on carbon (11.6
also found that the mandelate salt was a robust solid; it
was expected that the nature of the recrystallization from
g) under nitrogen, and the mixture was shaken under 55 psi of H2
overnight. The mixture was filtered through celite and the solvent
acetonitrile would allow for some tolerance in the purity
of the intermediates without suffering appreciable yield was used immediately. The product was dissolved in THF (2.5 L).
losses. Our expectations were realized when the desired Aq sat. NaHCO (3 L) and di-tert-butyldicarbonate (115.3 g, 0.53
mol) were added with THF (500 mL) and the mixture was stirred for
8 h. The mixture was partitioned between H O (1 L) and EtOAc (2
concentrated in vacuo to give 72.1 g of a yellow-green solid that
3
diastereomer 9 was obtained, from this three-step opera-
4
2
tion, in 21% yield with excellent optical purity.
L) and the layers separated. The aqueous layer was back-extracted
Our research has resulted in a successful scale-up of race- with EtOAc (500 mL). The combined organics were washed with
mic piperidine 2 and a method for the isolation of a single dilute HCl (0.5 N, 1 L) and brine (1 L), dried over MgSO and con-
4
centrated in vacuo. The residue was adsorbed onto silica gel (92 g)
and purified by silica gel flash chromatography (1.9 kg), eluting by
gradient of 25–40% EtOAc in hexane, to give 56.6 g of 4 as a clear
oil.
enantiomer of 2. The initial process required a Boc pro-
tecting group on the nitrogen. Although this facilitates the
chiral HPLC isolation of the enantiomers and provided in-
creased shelf stability of product 7, it did require the te-
dious operation of removal of the protecting group before
use. A modified process that utilized a diastereomeric
crystallization to separate the desired isomer was then de-
veloped. We further developed an alternative process to
rac-2 starting from 10 and 11, which made use of less po-
lymerization-prone intermediates. Our results further
1
H NMR (300 MHz, CDCl ): d = 4.04 (s, 2 H), 3.59 (t, J = 6.1 Hz,
3
2
H), 2.47 (t, J = 6.7 Hz, 2 H), 1.98 (m, 2 H), 1.47 (s, 9 H).
A mixture of THF (300 mL) and potassium tert-butoxide (309 mL,
M in THF) were stirred at r.t. while 4-fluorobenzyltriphenylphos-
1
phonium chloride (5, 134.1 g, 0.330 mol) was added in portions
over 13 min. The resulting ylide was stirred for 45 min, and a solu-
tion of 4 (56.6 g, 0.281 mol) in THF (150 mL) was added in a small
demonstrated resolution by fractional crystallization of a steady stream over 28 min while maintaining 20 °C with an ice-wa-
stable salt of 2, namely the (R)-mandelate 9, which elimi- ter bath. The mixture was stirred to r.t. overnight. The reaction was
partitioned between H O and EtOAc (1.5 L each), and the aqueous
nated the need for a Boc group altogether, thus providing
an opportunity to lower the costs associated with the pro-
2
layer extracted with EtOAc (500 mL). The combined organics were
washed with brine (500 mL), dried over MgSO , filtered and the
4
Synthesis 2005, No. 1, 92–96 © Thieme Stuttgart · New York

PAPER
Efficient Preparation of (3S)-3-(4-Fluorobenzyl)piperidinium Mandelate
95
1
solvents removed in vacuo. The residue was purified by flash chro-
matography on a column of silica gel (2 kg), eluting with 10%
EtOAc in hexane, to give 75.0 g of 6 as a yellow oil.
1
H NMR (300 MHz, CDCl ): d = 8.57 (d, J = 2.0 Hz, 1 H), 8.48 (dd,
3
J = 5.0, 2.0 Hz, 1 H), 7.70–7.66 (m, 1 H), 7.37–7.24 (m, 3 H), 7.08–
7.00 (m, 2 H), 5.87 (d, J = 3.0 Hz, 1 H), 2.91 (d, J = 3.0 Hz, 1 H).
13
H NMR (300 MHz, CDCl , 4:3 ratio of isomers A and B): d = 7.19
C NMR (75 MHz, CDCl ): d = 162.19 (d, J = 246 Hz), 147.72,
3
3
(
4
(
m, 2 H), 7.03 (m, 2 H), 6.36 (s, 1 Ha), 6.27 (s, 1 Hb), 4.14 (s, 2 Hb),
.00 (s, 2 Ha), 3.50 (t, 2 H), 2.47 (ddd, 2 Ha), 2.38 (ddd, 2 Hb), 1.71
m, 2 Hb), 1.61 (m, 2 Ha), 1.49 (s, 9 Ha), 1.34 (br s, 9 Hb).
140.19, 139.40, 134.65, 128.32, 128.21, 123.60, 115.43 (d, J = 22
Hz), 72.86.
19
F NMR (75 MHz, CDCl ): d = –114.93.
3
To a solution of olefin 6 (74.9 g, 0.254 mol) in EtOH (1.2 L) was
added 10% palladium on carbon (15.9 g) and the mixture was shak-
en under 55 psi of H at r.t. overnight. The mixture was filtered
2
+
MS (ESI ): m/z (%) = 245 (M + H + CH CN, 94), 204 (M + H, 100).
3
+
HRMS: m/z calcd for C H FNO : 204.0824; found: 204.0819.
12 11
through celite and the solvent removed in vacuo to give 70.7 g of
rac-7 as a clear oil.
Anal. Calcd for C H FNO: C, 70.93; H, 4.96; N, 6.89; F, 9.36.
10
Found: C, 70.65; H, 5.04; N, 6.71; F, 9.68.
1
2
1
H NMR (300 MHz, CDCl ): d = 7.10 (m, 2 H), 6.99 (t, J = 8.6 Hz,
3
H), 3.88 (br dt, J = 13.2, 4.0 Hz, 2 H), 2.78 (m, 1 H), 2.57–2.38
m, 3 H), 1.76–1.45 (m, 3 H), 1.42 (s, 10 H), 1.11 (br m, 1 H).
In the through-process without isolation of 12, the solvents were re-
duced to half-volume, and 4 N HCl in dioxane (288 mL, 1.5 equiv)
was added with stirring. The solids were filtered and washed with
2
(
1
3
Et O and hexane, and dried at 50 °C, yielding 140.57 g of solid. The
2
C NMR (75 MHz, CDCl ): d = 161.40 (d, J = 242 Hz), 159.78,
3
HCl salt 12a was recrystallized from MeCN (2.4 L) to give 111.2 g
of 12a as a white solid in 60% yield.
1
4
54.86, 135.51, 130.35, 130.25, 115.00 (d, J = 21 Hz), 79.23, 49.39,
4.47, 39.30, 37.77, 30.61, 28.43, 24.84 (extra peaks).
1
+
MS (AP ): m/z (%) = 279 (M + H + CH CN – C H , 100), 294 (M
H NMR (300 MHz, MeOH-d ): d = 8.91 (t, J = 1.0 Hz, 1 H), 8.74
4
3
4
8
(
t, J = 6.0 Hz, 1 H), 8.56 (dd, J = 9.0, 1.0 Hz, 1 H), 8.03 (dd, J = 9.0,
+
H, 50), 335 (M + H + CH CN, 24).
3
6
4
.0 Hz, 1 H), 7.49–7.42 (m, 2 H), 7.14–7.06 (m, 2 H), 6.02 (s, 1 H),
.88 (s, 2 H).
Anal. Calcd for C H FNO : C, 69.60; H, 8.26; N, 4.77; F, 6.49.
1
Found: C, 69.37; H, 7.95; N, 4,75; F, 6.86.
7
24
2
1
3
C NMR (75 MHz, MeOH-d ): d = 162.56 (d, J = 246 Hz), 145.89,
4
144.60, 140.03, 138.99, 138.50, 128.67, 127.07, 115.28, (d, J = 22
Hz), 71.16.
Separation of rac-7 into Respective Enantiomers
The separation was accomplished using a Chiralcel OJ column with
an isocratic solvent mixture of 10% BuCl in hexane. The first peak
19
F NMR (75 MHz, MeOH-d ): d = –116.36.
4
2
that eluted was the 7(S) isomer, R 11.999 min, [a] –2.7
5
t
D
+
MS (ESI ): m/z (%) = 245 (M + H + CH CN, 100), 204 (M + H, 93).
3
(c = 0.106, MeOH), >99% ee. The second peak off was the 7(R) iso-
mer, R 14.01 min., [a] +2.8 (c = 0.114, MeOH), 98% ee. The
spectral data were identical to that reported for the racemate.
2
5
+
11FNO : 204.0824; found: 204.0832.
HRMS: m/z calcd for C12
H
t
D
Anal. Calcd for C H FNO·HCl·0.1H O: C, 59.69; H, 4.67; N,
1
2
10
2
5.80; F, 7.87; Cl, 14.68. Found: C, 59.69; H, 4.27; N, 5.74; F, 7.90;
Cl, 14.66.
Salt Screening Method for rac-2
A mixture of rac-2 (193 mg, 1.0 mmol) with either (R)-(–)-mandel-
ic acid or (R)-(–)-phenylpropionic acid (1 mmol) were combined in
Et O (5 mL). The PPA salt was soluble in Et O or chlorobutane. The
(3S)-3-(4-Fluorobenzyl)piperidine (rac-2) and its Mandelate
Salt (9)
2
2
mandelic acid salt was insoluble, filtered and dried to provide 0.28
g of 8a: mp 134–144 °C. This diastereomeric mixture was recrys-
tallized from MeCN to provide 0.15 g of 9: mp 161–164 °C. The
A solution of 12a (119.8 g, 0.50 mol) in EtOH (1.5 L) was charged
with PtO (5 g) and hydrogenated on a Parr apparatus at 50 psi for
5 h. The catalyst was removed by filtration through celite and the
filtrate concentrated in vacuo. The resulting oil (14) was dissolved
2
free base was prepared by dissolving 9 in H O, the aqueous solution
2
made basic with Na CO and extraction with Et O (10 mL). The res-
2
3
2
in MeCN (1.5 L) and used without purification.
2
idue, 0.058 g, was found to have a rotation of [a]D +5.0 (c = 1.162,
5
A mixture of NaI (149.9 g, 1.00 mol) and MeCN (1500 mL) was
stirred until dissolved. Chlorotrimethylsilane (130.37 g, 1.2 mol)
was added in one portion, the mixture was stirred for 15 min and the
MeCN solution of 14 was added via addition funnel. The reaction
was warmed to 60 °C under a reflux condenser overnight. The reac-
EtOH). For ee determination, the free base from another experiment
(0.28 g, 1.45 mmol) was converted into 7 using a mixture of THF
(10 mL), aq sat. NaHCO (5 mL), and di-tert-butyldicarbonate (0.41
g, 1.88 mmol). After 2 h at r.t., the mixture was extracted with Et O
3
2
(
(
10 mL), dried, evaporated and purified by flash chromatography
16 g silica gel) using 10% EtOAc in hexane. The product fraction,
tion was concentrated in vacuo, diluted with Et O and the organics
2
were washed with aq NaOH (2 N). The organic layer was dried over
MgSO and concentrated in vacuo. The crude rac-2 (75.9 g, 0.39
mol) was dissolved in warm (70 °C) MeCN (450 mL), to which was
added a warm (70 °C) solution of (R)-(–)-mandelic acid (62.4 g,
0
.27 g, was collected and analyzed using the chiral HPLC method
reported above. The ee measurement was 78% favoring the desired
(S) isomer.
4
7
0
.41 mol) in MeCN (250 mL). The mixture was allowed to cool to
(
4-Fluorophenyl)(pyridin-3-yl)methanol (12), HCl Salt (12a)
r.t. overnight. The solid was filtered and washed with cold MeCN.
The crude salt (54.9 g) was recrystallized from MeCN (3.4 L) to
provide 37.44 g of 9 in 21% yield.
A solution of 4-fluorophenyl magnesium bromide (800 mL, 1 M in
THF) was added to a solution of 3-pyridinecarboxaldehyde (82.5 g,
0
.77 mol) in Et O (1.5 L) keeping an internal temperature of –40 °C.
2
2
Mp 172–173 °C; [a]D –36.3 (c = 0.806, EtOH), 97% ee.
5
The reaction was allowed to gradually warm to 0 °C and quenched
with a dilute aq NH Cl solution (1/3 sat., 2/3 H O). The mixture was
extracted with Et O, the combined organics washed with H O, brine
4
2
–1
IR (KBr): 1605, 1508, 1375 cm .
2
2
1
and dried over MgSO . The solvents were removed in vacuo to give
4
H NMR (300 MHz, MeOH-d ): d = 7.43 (dd, J = 8.0, 1.5 Hz, 2 H),
4
1
40.39 g of 12, as a yellow oil, in 89% yield. A small sample was
7.28–7.12 (m, 5 H), 6.99 (dd, J = 8.0, 1.5 Hz, 2 H), 4.86 (s, 1 H),
3.19 (br d, 1 H), 3.10 (br d, 1 H), 2.72 (dt, J = 12.8, 3.3 Hz, 1 H),
2.55–2.47 (m, 3 H), 19.3 (m, 1 H), 1.75 (m, 2 H), 1.65–1.51 (m, 1
H), 1.14 (m, 1 H).
purified by silica gel column chromatography using 33–100%
EtOAc in hexane.
–
IR (film): 3600–2700, 1603, 1507, 1223 cm .
1
Synthesis 2005, No. 1, 92–96 © Thieme Stuttgart · New York

9
6
G. C. Emmett et al.
PAPER
1
3
C NMR (75 MHz, MeOH-d ): d = 178.26, 161.65 (d, J = 242 Hz), References
4
142.18, 134.36, 130.39, 130.29, 127.69, 126.91, 126.52, 114.73 (d,
J = 21 Hz), 74.80, 43.82, 38.58, 35.35, 28.16, 21.86.
(
(
1) Zhou, Z.-L.; Keana, J. F. W. J. Org. Chem. 1999, 64, 3763.
2) (a) Ko, S. S.; Duncia, J. V. K.; Santella, J. B.; Wacker, D. A.;
Kim, U. T. PCT Int. Appl. WO 0035454 A1, 2000; Chem.
Abstr. 2000, 133, 43445. (b) Ko, S.; Clark, C. M.; Delucca,
G. V.; Duncia, J. V.; Santella, J. B.; Wacker, D. A. PCT Int.
Appl. WO 0035453 A1, 2000; Chem. Abstr. 2000, 133,
43444. (c) Ko, S. S.; Delucca, G. V.; Duncia, J. V.; Kim, U.
T.; Santella, J. B. I.; Wacker, D. A. PCT Int. Appl. WO
1
9
F NMR (75 MHz, MeOH-d ): d = –119.29.
4
+
MS (ESI ): m/z (%) = 194 (M + H, 100).
+
HRMS: m/z calcd for C H FN : 194.1360; found: 204.1345.
1
2
17
Anal. Calcd for C H FNO : C, 69.55; H, 7.00; N, 4.06. Found: C,
3
20
24
6
9.51; H, 6.87; N, 3.92.
0035452 A1, 2000; Chem. Abstr. 2000, 133, 43443. (d) Ko,
S. S.; Delucca, G. V.; Duncia, J. V.; Santella, J. B.; Wacker,
D. A.; Watson, P. S.; Varnes, J. G. PCT Int. Appl. WO
Acknowledgment
0035451 A1, 2000; Chem. Abstr. 2000, 133, 43442. (e) Ko,
S. S.; Delucca, G. V.; Duncia, J. V.; Santella, J. B.; Gardner,
D. S. PCT Int. Appl. WO 0035449 A1, 2000; Chem. Abstr.
2000, 133, 43441.
We thank the Spectroscopy group for technical support in com-
pound characterizations, J-Star Research Inc., for additional experi-
mental details and Dr. Carl P. Decicco for helpful discussions
throughout this work.
(
(
3) Pedrosa, R.; Andres, C.; Duque-Soladana, J. P.; Roson, C. D.
Tetrahedron: Asymmetry 2000, 11, 2809.
4) Bottcher, H.; Prucher, H.; Greiner, H.; Barber, A.; Martinez,
J.-M. PCT Int. Appl. WO 9857953, 1999; Chem. Abstr.
1999, 130, 81409.
(
5) Brehm, L.; Krogsgaard-Larsen, P.; Schaumburg, K.;
Johansen, J. S.; Falch, E.; Curtis, D. R. J. Med. Chem. 1986,
29, 224.
(6) The absolute stereochemistry was confirmed as shown, and
will be addressed in a series of forthcoming papers.
(7) Cain, G. A.; Holler, E. R. Chem. Commun. 2001, 1168.
Synthesis 2005, No. 1, 92–96 © Thieme Stuttgart · New York