Enantioselective synthesis and absolute configuration of (-)-1-(benzofuran-2-yl)-2-propylaminopentane, ((-)-BPAP), a highly potent and selective catecholaminergic activity enhancer

Article abstract of DOI:10.1016/S0968-0896(00)00341-2

Enantioselective synthesis and absolute configuration of (-)-1-(benzofuran-2-yl)-2-propylaminopentane ((-)-BPAP), which is a highly potent and selective catecholaminergic activity enhancer (CAE) substance, are described. The synthetic approach consists of the coupling reaction of benzofuran with (R)-N-tosyl-2-propylazirizine or (R)-N-methoxy-N-methylnorvaliamide, followed by appropriate modifications of the resulting coupling products. As the results, (-)-BPAP turned out to have the R configuration, which was finally confirmed by X-ray crystallographic analysis.

Full text of DOI:10.1016/S0968-0896(00)00341-2

Bioorganic & Medicinal Chemistry 9 (2001) 1213±1219
Enantioselective Synthesis and Absolute Con®guration of
(À)-1-(Benzofuran-2-yl)-2-propylaminopentane, ((À)-BPAP),
a Highly Potent and Selective Catecholaminergic
Activity Enhancer
Takahiro Oka,a Takuya Yasusa,a Takashi Ando,a Mayumi Watanabe,a
Fumio Yoneda,a,* Toshimasa Ishidab and Joseph Knollc
aResearch Institute, Fujimoto Pharmaceutical Corporation, 1-3-40, Nishiotsuka, Matsubara, Osaka 580-8503, Japan
bOsaka Universzity of Pharmaceutical Science, 4-20-1, Nasahara, Takatsuki, Osaka 569-1094, Japan
cDepartment of Pharmacology, Semmelweis University of Medicine, P.O.B. 370, Budapest H-1445, Hungary
Received 1 November 2000; accepted 8 December 2000
AbstractÐEnantioselective synthesis and absolute con®guration of (À)-1-(benzofuran-2-yl)-2-propylaminopentane ((À)-BPAP),
which is a highly potent and selective catecholaminergic activity enhancer (CAE) substance, are described. The synthetic approach
consists of the coupling reaction of benzofuran with (R)-N-tosyl-2-propylazirizine or (R)-N-methoxy-N-methylnorvaliamide, fol-
lowed by appropriate modi®cations of the resulting coupling products. As the results, (À)-BPAP turned out to have the R con®g-
uration, which was ®nally con®rmed by X-ray crystallographic analysis. # 2001 Elsevier Science Ltd. All rights reserved.
Introduction
inhibition, (À)-1-phenyl-2-propylaminopentane ((À)-
PPAP) devoid of MAO-B inhibition was synthesized.
Actually (À)-PPAP showed the CAE activity by
enhancing the impulse mediated propagation release of
cathecholamines rather more potent than (À)-deprenyl.
Aiming to develop a selective substance much more
potent than (À)-deprenyl or (À)-PPAP, we have
designed and synthesized a series of new 1-aryl-2-pro-
pylaminopentanes by changing the benzene ring of
PPAP, and we have found that 1-(benzofuran-2-yl)-2-
propylaminopentane (BPAP) was a highly potent and
selective CAE substance devoid of the MAO-B inhibi-
tory e€ect (Chart 1).10a
The performance of catecholaminergic neurons in the
brain has been proposed to be controlled according to
the physiological need via a catecholaminergic activity
enhancer (CAE) mechanism.1 This novel CAE mecha-
nism can reasonably elucidate the e€ects of the brain
endogenous amines such as phenylethylamine (PEA)
and tryptamine which signi®cantly enhance the impulse
mediated propagation release of catecholamines from
the catecholaminergic neurons.2 A PEA derivative, (À)-
deprenyl (selegiline), known as a selective inhibitor of B-
type monoamine oxidase (MAO-B),3 is for the time
being the only CAE substance in clinical use.4 The
unique e€ects of (À)-deprenyl such as the prolongation
of the life of rats,5 the neuroprotective e€ect,6 the slow-
ing of the functional decline of otherwise untreated
subjects with early Parkinson's disease,7 and the slowing
of the progression of Alzheimer's disease,8 were attrib-
uted to the CAE e€ect of this drug.9
BPAP was originally synthesized as follows by starting
from 1-(benzofuran-2-yl)-2-nitropentene (2) prepared
by the condensation of benzofuran-2-carbaldehyde and
1-nitrobutane. Reduction of 2 with lithium aluminum
hydride gave the corresponding 2-aminopentane (3),
which was treated with propionyl chloride to a€ord the
N-{2-[1-(benzofuran-2-yl)pentyl]}propionamide (4). The
propionamide 4 was reduced with aluminum hydride to
give BPAP (1) (Scheme 1).10b
To furnish a direct evidence that the CAE activity with
a small dose of (À)-deprenyl is unrelated to MAO-B
As BPAP (1), however, contains an asymmetric carbon
atom, the optical resolution into the corresponding (À)-
*Corresponding author. Tel.: +81-723-32-5151; fax: +81-723-32-
8482; e-mail: soyaku@fujimoto-pharm.co.jp
0968-0896/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(00)00341-2

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T. Oka et al. / Bioorg. Med. Chem. 9 (2001) 1213±1219
Chart 1.
Scheme 1. Reagents and conditions: (a) n-BuNO2, AcONH4, AcOH, 100 ꢀC; (b) LiAlH4, THF, rt; (c) EtCOCl, CH2Cl2, rt; (d) AlH3, Et2O, rt.
Scheme 2. Reagents and conditions: (a) LiAlH4, THF, re¯ux; (b) TsCl, Py, 0 ꢀC; (c) Et2O, aq NaOH, 0 ꢀC; (d) (1) n-BuLi, THF, benzofuran, 0 ꢀC,
(2) 8; (e) NaH (via (R)-9), PrBr, DMF, 70 ꢀC; (f) Sodium naphthalide, DME, À78 ꢀC.
and (+)-enantiomer, ((À)-BPAP and (+)-BPAP), was
carried out by HPLC on a chiral stationary phase. The
(À)-BPAP thus obtained turned out to be about 50
times or more potent than (+)-BPAP, (À)-deprenyl or
(À)-PPAP as a CAE substance.10a We report here a
novel enantioselective synthesis of (À)-BPAP which is
based on readily available norvaline as starting material
and determination of the absolute con®guration of (À)-
BPAP.
of benzofuran with N-tosyl-2-propylaziridine (8)
(Method A) and N-benzyloxycarbonylamino-N-meth-
oxy-N-methyl norvalinamide (13) (Method B), followed
by appropriate modi®cations of the resulting coupling
products, as outlined in Schemes 2 and 3. Racemic 1
was obtained in the same way starting from dl-norvaline.
Method A. Condensed furans such as benzofuran can be
lithiated at the a-position more readily than that at any
other possible positions and treated with electrophiles to
a€ord the corresponding a-substituted derivatives.11
Thus, the coupling of lithiated benzofuran with N-tosyl-
2-propylaziridine (8), prepared from norvaline (5) by the
known methodology,12 gave the desired 1-(benzofuran-
2-yl)-2-(p-toluenesulfonyl)aminopentane (9). Treatment
of the amide 9 with bromopropane in the presence of
Synthesis
Since the structure of BPAP (1) contains a 2-amino-
pentane unit, we considered the use of norvaline as a
chiral building block in the synthesis of the respective
(R)- and (S)-enantiomers. Thus, we have developed two
synthetic approaches consisting of the coupling reaction

T. Oka et al. / Bioorg. Med. Chem. 9 (2001) 1213±1219
1215
NaH, followed by removement of N-tosyl group a€or-
ded 1, which was converted into the corresponding
hydrochloride. Furthermore, lithium salt of 9 (11)
obtained directly in the coupling reaction also gave 1 by
the treatment with bromopropane without NaH.
lithium aluminum hydride (LiAlH4) to give 1, which
was converted into the corresponding hydrochloride.
Determination of the absolute con®guration
The syntheses of both enantiomers of BPAP (1)
according to Schemes 2 and 3 were ascertained to pre-
serve the chirality of the starting materials. Namely, the
speci®c rotation of (R)-1ꢁ HCl was [a]D20 À4.23ꢀ (c 4.40,
methanol) and that of (S)-1ꢁ HCl was [a]D20 +5.11ꢀ (c
0.440, methanol), which were identical with those of
each enantiomers resoluted from racemic 1 by HPLC on
a chiral stationary phase.15 Accordingly, (À)-1 was
determined to have the R con®guration. Finally, the
structure of crystal of (À)-1ꢁ HCl obtained by
recrystallization from ethanol and diethyl ether have
Method B. a-Lithiobenzofuran was treated with N-
amino-N-methoxy-N-methylnorvalinamide (13), pre-
pared by N-methoxy-N-methylamidation from norva-
line (5),13 gave the desired 1-(benzofuran-2-yl)-2-
benzyloxycarbonylamino-1-pentanone (14). Treatment
of the pentanone 14 with Et3SiH in CF3COOH14 a€or-
ded 1-(benzofuran-2-yl)-2-aminopentane (3), which was
treated with propionyl choloride to a€ord the desired
N-{[2-(1-(benzofuran-2-yl))pentyl]}propionamide (4).
The propionamide 4 thus obtained was reduced with
Scheme 3. Reagents and conditions: (a) ZCl, aq NaOH, aq Na2CO3, 0 ꢀC!rt; (b) WSCDI, HOBt, CH2Cl2, MeONHMeꢁ HCl, À10 ꢀC!rt; (c) (1) n-
BuLi, THF, benzofuram, À30± À25 ꢀC; (2) 13, (d) CF3COOH, 50±55 ꢀC; (e) EtCOCl, CH2Cl2, rt; (f) LAH, Et2O, 0 ꢀC!rt.
Figure 1. ORTEP drawing of (R)-(À)-1ꢁ HCl.

1216
T. Oka et al. / Bioorg. Med. Chem. 9 (2001) 1213±1219
Table 1. Crystallographic data
GX-270 (270 MHz) spectrometer with tetramethylsilane
as internal reference and all shifts are indicated in ppm.
Electron impact (EI) mass spectra and high resolution
mass (HRMS) spectra were recorded on a Hitachi M-
80B mass spectrometer. Elemental analyses were per-
formed using a Yanagimoto MT-3 elemental analyzer.
Optical rotations were measured on a Horiba SEPA-200
digital polarimeter. Column chromatography was per-
formed on silica gel (Fuji Silysia Chemical, particle size
0.053±0.150 mm).
Formula
Mr
Crystal system
Space group
Cell constant
a (A)
C16H23N1O1ꢁ HCl
281.83
Monoclinic
P21
10.411(1)
7.533(1)
11.029(2)
90.00
105.98(1)
90.00
831.6(1)
2
1.125
b (A)
c (A)
a (ꢀ)
b (ꢀ)
g (ꢀ)
Volume (A3)
Z
Materials. Organic reagents and solvents were pur-
chased from Tokyo Kasei Kogyo Co. Ltd., Nakarai
Tesque, Inc., Wako Pure Chemical Industries, Ltd., and
Aldrich Chemical Co., and used as received.
D (calc), g cmÀ3
m (Cu Ka) (mmÀ1
F (000)
Crystal size (mm)
)
1.97
304
0.5Â0.2Â1.0
Data collection method
Scan spped in o, ꢀ minÀ1
Scan range in o, ꢀ
o-2y scan
12
All of the respective (R), (S), and dl products were
sythesized, but only preparation of (R) products are
described below.
1.600+0.3tany
Dataꢀrange measured
0ꢂhꢂ12, À9ꢂkꢂ0, À13ꢂlꢂ13
ymax
,
67.61
1608
1478
No. of independent re¯ections
No. of observed re¯ections
Criterion for observed re¯ections
No. of parameters
Goodness of ®t
R; Rw
(R)-2-Amino-1-pentanol (R)-6. d-Norvaline (R)-5 (15.0
g, 128 mmol) was added in portions into a suspension of
lithium aluminum hydride (7.3 g, 192 mmol) in tetra-
hydrofuran (230 mL) under stirring at 0 ꢀC, and the
mixture was re¯uxed for 2 h. After being cooled, water
was added to the mixture until ®nishing the evolution of
hydrogen. The insoluble matter was ®ltrated o€ and
washed with ethyl acetate (150 mLÂ4). The combined
®ltrate was dried over anhydrous sodium sulfate and
evaporated to dryness under reduced pressure. The oily
residue was distilled (115 ꢀC/ 34 mmHg) to give (R)-6.
(8.3 g, 63%) asꢀcolorless needles: (lit.16 (S): mp 45±
I>2s(I)
172
1.308
0.041; 0.145
been revealed by X-ray crystallography. The ORTEP
drawing is illustrated in Figure 1, and the crystal-
lographic data are summarized in Table 1. From the
X-ray crystallographic analysis of (À)-1ꢁ HCl, by means
of anomalous dispersion e€ect of the chlorine atom, it
has been con®rmed that (À)-1 has the R con®guration.
47 ꢀC) [a]D20 À4.1 (c 1.4, methanol); H NMR(CDCl3)
1
0.93 (t, J=6.7 Hz, 3H), 1.12±1.54 (m, 4H), 1.90±2.40
(br, 3H), 2.76±2.90 (m, 1H), 3.26 (dd, J=10.8, 8.1 Hz,
1H), 3.58 (dd, J=10.8, 4.0 Hz, 1H); IR (KBr) 3320,
2940, 1460 cmÀ1; HRMS (EI) m/z calcd for C5H13NO
(M+), 103.0997; found 103.0948.
Conclusion
Two ecient enantioselective routes toward (À)-BPAP
((À)-1) have been developed starting from commercially
available (R)-norvaline. Thus, the productibity of (À)-
BPAP was much improved by use of these routes in
comparison with the previous synthetic route10b by the
optical resolution of racemic 1. The absolute con®gura-
tion of (À)-BPAP has been determined to be R by the
enantioselective synthesis and X-ray crystallographic
analysis. It is interesting to note that the known CAE
substances such as (À)-deprenyl, (À)-PPAP, and (À)-
BPAP have all the R con®gurations. This fact suggests
that the CAE substances would interact with a speci®c
bioactive point of catecholaminergic neurons in the
brain. Utilization of these routes for mass production
and development of methods using further asymmetric
induction are currentry underway in our laboratory.
(R)-2-Amino-1-pentanol-bis-p-tolenesulfonate (R)-7. To a
solution of (R)-6 (8.2 g, 79 mmol) in pyridine (50 mL)
was added p-toluenesulfonyl chloride (36.4 g, 191
mmol) at 0 ꢀC under stirring, and the mixture was stir-
red at 0 ꢀC for 2.5 h. Diethyl ether (250 mL) was added
to the reaction mixture, and the organic phase was
washed with 4 M HCl aq solution (70 mLÂ3), and then
water (50 mL). The organic layer was used for the next
reaction without puri®cation.
Colorless needles; mp 58±60 ꢀC (from chloroform); [a]2D0
+51ꢀ (c 1.0, methanol), 1H NMR (CDCl3) 0.72 (t,
J=7.1 Hz, 3H), 0.90±1.50 (m, 4H), 2.42 (s, 3H),2.46 (s,
3H), 3.30±3.40 (m, 1H), 3.82 (dd, J=10.1, 4.4 Hz, 1H),
3.95 (dd, J=10.1, 3.3 Hz, 1H), 4.79 (d, J=8.4 Hz, 1H),
7.25±7.37 (m, 4H), 7.71 (t, J=8.1 Hz, 4H); IR (KBr)
3275, 2880, 1595, 1365, 1310, 1180, 1160 cmÀ1; MS 410
(M+±1), 365, 329, 299, 255, 225, 183. Anal. calcd for
C19H25NO5S2: C, 55.45; H, 6.12; N 3.40%. Found: C,
55.23; H, 6.10; N 3.12%.
Experimental
Instruments. Melting points (mp) were obtained on a
Yanagimoto micromelting point apparatus and are
uncorrected. Infrared (IR) spectra were recorded on a
Hitachi 260±50 spectrometer. Proton nuclear magnetic
resonance (1H NMR) spectra were recorded on a JEOL
(R)-N-(p-Toluenesulfonyl)-2-propylaziridine (R)-8. To
the above ether solution of (R)-7 (250 mL) was added
2.5 M NaOH aq solution (250 mL) dropwise at 0 ꢀC,

T. Oka et al. / Bioorg. Med. Chem. 9 (2001) 1213±1219
1217
and the mixture was stirred at 0 ꢀC for 1.5 h. The reac-
tion mixture was allowed to stand to separate the
organic phase. The organic phase was washed with
water (50 mL) and brine (50 mL), dried over anhydrous
sodium sulfate, and concentrated in vacuo. The residue
was puri®ed by silica gel column chromatography (n-
hexane:ethyl acetate=6:1) to give (R)-8 (16.4 g, 86%) as
colorless oil: [a]2D0 À15ꢀ (c 1.3, chloroform) (lit.17 (S):
Anal. calcd for C23H29NO3S: C, 69.14; H, 7.32; N
3.51%. Found: C, 69.02; H, 7.25; N 3.15%.
(R)-1-(Benzofuran-2-yl)-2-propylaminopentane
(R)-1
hydrochloride. To a solution of naphthalene (17.8 g,
139 mmol) in ethylene glycol dimethylether (90 mL) was
added sodium (3.26 g, 139 mmol) at room temperature
under argon atomosphere, and the mixture was soni-
cated for 2 h. The solution was added dropwise into a
solution of (R)-10 (13.9 g, 34.8 mmol) in ethylene glycol
dimethylether (70 mL) at À78 ꢀC, and was stirred at
À78 ꢀC for 30 min. To the solution was added water
until the color of the solution changes to orange. To the
solution was added diethyl ether (300 mL) and the
organic phase was separated. The organic phase was
extacted with 2 M HCl aq solution (120 mLÂ5). After
washing the aq layer with diethyl ether (100 mL), the
layer was made basic to litmus with 28% aqueous NH3.
The aqueous mixture was extracted with diethyl ether
(400 mL). The organic phase was dried over anhydrous
sodium sulfate and concentrated in vacuo to give (R)-1
(5.84 g, 68%), which was treated with HCl in diethyl
ether to give (R)-1 hydrochloride (5.97 g, 61%) as col-
orless needles: mp 167±168 ꢀC (from ethanol-diethyl
ether); [a]2D0 À4.23ꢀ (c 4.40, methanol); 1H NMR
(CDCl3) 0.91 (t, J=7.4 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H),
1.35±1.72 (m, 2H), 1.72±2.15 (m, 4H), 2.75±3.05 (m,
2H), 3.20±3.35 (m, 1H), 3.45±3.64 (m, 2H), 6.65 (s, 1H),
7.10±7.38 (m, 2H), 7.38±7.65 (m, 2H), 9.62 (br, 2H),
[a]2D0 +12ꢀ(c 0.97, CHCl3)); H NMR (CDCl3) 0.87 (t,
1
J=7.1 Hz, 3H),1.23±1.61 (m, 4H), 2.06 (d, J=4.7 Hz,
1H), 2.45 (s, 3H), 2.63 (d, J=7.1 Hz, 1H), 2.67±2.83 (m,
1H), 7.34 (d, J=8.4 Hz, 2H), 7.83 (d, J=8.4 Hz, 2H);
IR (neat) 2960, 1592, 1459, 1323 cmÀ1; HRMS (EI) m/z
calcd for C12H17NSO2 (M+), 239.0980; found 239.1027.
(R)-1-(Benzofuran-2-yl)-2-(p-toluenesulfonyl)aminopen-
tane (R)-9. To a solution of benzofuran (2.68 g, 22.8
mmol) in diethyl ether (20 mL) was added n-butyl-
lithium (1.54 M in hexane, 14.8 mL, 22.8 mmol) at 0 ꢀC
under argon atomosphere, and the mixture was re¯uxed
for 30 min. (R)-8 (1.82 g, 7.60 mmol) in diethyl ether (15
mL) was added herein at 0 ꢀC and the mixture was stir-
red at room temperature for 2 h. After adding water (30
mL) at 0 ꢀC, the organic phase was separated, dried over
anhydrous sodium sulfate, and concentrated in vacuo.
The residue was puri®ed by silica gel column chroma-
tography (n-hexane:ethyl acetate=5:1) to give (R)-9
(2.01 g, 74%) as colorless needles: mp 83±84 ꢀC(from n-
hexane); [a]2D0 À38ꢀ (c 1.0, methanol), 1H NMR (CDCl3)
0.83 (t, J=7.1 Hz, 3H), 1.26±1.65 (m, 4H), 2.33 (s, 3H),
2.77 (dd, J=15.1, 6.1 Hz, 1H), 2.84 (dd, J=15.1, 5.4
Hz, 1H), 3.55±3.70 (m, 1H), 4.55 (d, J=8.4 Hz, 1H),
6.33 (s, 1H), 7.10 (d, J=8.1 Hz, 2H), 7.14±7.30 (m, 2H),
7.35 (d, J=8.1 Hz, 1H), 7.44 (dd, J=6.4, 2.0 Hz, 1H),
7.65 (d, J=8.1 Hz, 2H); IR (KBr) 3290, 2925, 1602,
1453, 1409, 1323 cmÀ1; MS 357(M+), 226, 186, 155.
Anal. calcd for C20H23NO3S:C, 67.20; H, 6.49; N 3.92%.
Found: C, 67.45; H, 6.55; N, 3.59%.
IR(KBr) 2960, 2750, 2510, 2430, 1608, 1595, 1457 cmÀ1
;
MS 245(M+). Anal. calcd for C16H23NOꢁ HCl:C, 68.19;
H, 8.58; N:4.97%. Found: C:68.36; H, 8.42; N: 5.06%.
Lithium( R)-1-(Benzofuran-2-yl)-2-N-propyl-p-toluene-
sulfonylaminopentane (R)-11. To a solution of benzo-
furan (6.86 g, 59.4 mmol) in tetrahydrofuran (20 mL)
was added n-butyllithium (1.50 M in hexane, 39.6 mL,
59.4 mmol) at 0 ꢀC under argon atomosphere, and the
mixture was re¯uxed for 30 min. To the solution was
added (R)-8 (11.8 g, 49.5 mmol) in tetrahydrofuran (17
mL) for 20 min, and the mixture was stirried at 0 ꢀC.
After 10 min, the precipitate was resulted and diethyl
ether (20 mL) was added to the mixture at 0 ꢀC. The
mixture was ®ltered and washed with diethyl ether (50
mLÂ4) to give (R)-11 (12.5 g, 70%) as yellow solid: mp
(R)-1-(2-Benzofuran-2-yl)-2-N-propyl-p-toluenesulfonyl-
aminopentane (R)-10. To a solution of (R)-9 (9.60 g,
26.9 mmol) in dimethylformamide (100 mL) was added
NaH (1.61 g, 40.3 mmol) under stirring at 0 ꢀC. Bro-
mopropane (3.7 mL, 40.3 mmol) was added to the mix-
ture and then stirred at 70 ꢀC for 1 h. The reaction
mixture was poured over ice water (200 mL) and stirred
at room temperature for 15 min. The precipitate was
collected by ®ltration, and washed with water (50 mL)
to give (R)-10. The ®ltrate was extracted with diethyl
ether (150 mL), and the etheral solution was separated,
dried over anhydrous sodium sulfate, and concentrated
in vacuo. The residue was puri®ed by silica gel column
chromatography (n-hexane:ethyl acetate=9:1) to give
(R)-10, which was combined with the previous (R)-10 to
give the sum (R)-10 (8.97 g, 84%) as colorless needles;
mp 92.5±93.5 ꢀC (from n-hexane); [a]2D0 À104ꢀ (c 1.11,
ꢀ
1
230 C-(decompose); H NMR (CDCl3) 0.83 (t, J=7.1
Hz, 3H), 1.20±1.55 (m, 4H), 2.32 (s, 3H), 2.75 (dd,
J=15.1, 6.4 Hz, 1H), 2.85 (dd, J=15.1, 5.7 Hz, 1H),
3.54±3.69 (m, 1H), 6.33 (s, 1H), 7.08 (d, J=8.1 Hz, 2H),
7.14±7.49 (m, 4H), 7.64 (d, J=8.1 Hz, 2H); IR(KBr)
2970, 1600, 1460, 1325 cmÀ1; MS 363 (M+), 357, 226,
155, 130.
(R)-N-(Benzyloxycarbonyl)-norvaline (R)-12. d-Norva-
line (R)-5 (7.00 g, 59.8 mmol) was dissolved in 2M
NaOH aq solution (35 mL) under stirring at 0 ꢀC. To
the solution was benzyl chloroformate (10.2 g, 60 mmol)
and 2M Na2CO3 aq solution (53 mL). The mixture was
stirred for 30 min at 0 ꢀC and further stirred overnight
at room temperature. The reaction solution was acid-
i®ed with concentrated HCl, and extracted with diethyl
ether. The etheral phase was washed with water and
brine, dried over anhydrous sodium sulfate, and
1
methanol); H NMR (CDCl3) 0.83 (t, J=7.1 Hz, 3H),
0.89 (t, J=7.4 Hz, 3H), 1.15±1.86 (m, 6H), 2.31 (s, 3H),
2.72±2.88 (m, 1H), 2.98±3.16 (m, 1H), 4.14±4.27 (m,
1H), 6.35 (s, 1H), 7.08 (d, J=7.7 Hz, 1H), 7.13±7.30 (m,
2H), 7.39 (dd, J=7.7, 1.3 Hz, 1H), 7.44 (dd, J=6.7, 2.0
Hz, 1H), 7.63 (d, J=7.4 Hz, 2H); IR (KBr) 2950, 1593,
1450, 1325 cmÀ1; MS 399(M+), 269, 226, 155, 130.

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T. Oka et al. / Bioorg. Med. Chem. 9 (2001) 1213±1219
concentrated in vacuo to give (R)-12 (11.1 g, 74%) as
white solid: mp 84±85 ꢀC (from ethyl acetate) (lit.18 (S):
mp 86 ꢀC); [a]2D0 +1.6ꢀ (c 9.1, methanol) (lit.18 (S): [a]1D2
(R)-1-(Benzofuran-2-yl)-2-aminopentane (R)-3 hydro-
chloride. To a solution of (R)-14 (1.50 g, 4.26 mmol) in
tri¯uoroacetic acid (6.60 mL) was added triethylsilane
(2.18 g, 18.8 mmol) at 0 ꢀC under stirring. The mixture
was stirred at 50±55 ꢀC for 2 h. The reaction mixture
was cooled to room temperature, to which a mixture of
water (1.0 mL) and methanol (1.0 mL) was added and
stirred overnight. The mixture was neutralized with
NaHCO3 and extracted with ethyl acetate (100 mLÂ3).
Combined organic extracts were washed with brine,
dried over anhydrous sodium sulfate, and concentrated
in vacuo. The residue was puri®ed by silica gel column
chromatography (n-hexane:dichloromethane=1:1) to
give (R)-3 (0.47 g, 54%), which was treated with HCl in
diethyl ether to give (R)-3 hydrochloride (0.42 g, 41%)
as colorless needles: mp 143±144 ꢀC (from acetone); [a]2D0
À15ꢀ (c 1.0, methanol); 1H NMR (CDCl3) 0.91 (t,
J=7.0 Hz, 3H), 1.35±1.80 (m, 4H), 3.10±3.40 (m, 2H),
3.68 (m, 1H), 6.56 (s, 1H), 7.10±7.42 (m, 2H), 7.47±7.51
(m, 2H), 7.64 (br, 2H); IR(KBr) 2800, 2680, 1585, 1510
cmÀ1; MS 204(M++1), 160, 131, 103, 72. Anal. calcd
for C13H17NO:C, 65.13; H, 7.57; N 5.84%. Found: C,
65.46; H, 7.49; N 5.96%.
À4.2ꢀ (c 2, acetone)); H NMR (CDCl3) 0.94 (t, J=7.1
1
Hz, 3H), 1.60±2.00 (m, 4H), 4.30±4.50 (m, 1H), 5.12 (s,
1H), 5.20±5.30 (m, 1H), 7.35 (s, 1H). IR(KBr) 3330,
1745, 1725, 1690, 1650 cmÀ1; MS 251(M+), 206, 162,
110. HRMS (EI) m/z calcd for C13H17NO4 (M+)
251.1157; found 251.1195.
(R)-N-Benzyloxycarbonylamino-N-methoxy-N-methyl
norvalinamide (R)-13. 1-Hydroxybenzotriazole hydrate
(1.88 g, 13.9 mmol) and 4-methylmorpholine (1.49 g,
14.7 mmol) were added to a À10 ꢀC solution of 1-ethyl-
3-[3-(diethylamino)propyl]carbodimide hydrochloride
(2.66 g, 13.9 mmol) in dichlomethane (70 mL). After the
reaction mixture was warmed to room temperatue, to
the mixture was added a solution of (R)-12 (3.50 g, 13.9
mmol) in dodichloromethane (28 mL). The mixture was
stirred at room temperature for 30 min and cooled to
À10 ꢀC. A mixture of N-methyl-O-methylhydroxyl-
amine hydrochloride (1.37 g, 14.1 mmol) and 4-methyl-
morpholine (1.62 mL, 14.7 mmol) in dichloromethane
(28 mL) was added dropwise, and stirred at room tem-
perature overnight. The reaction mixture was evapo-
rated and partitioned between water and ethyl acetate.
The organic layer was washed with 10% HCl, saturated
NaHCO3 and brine, then dried over anhydrous mag-
nessium sulfate, and concentrated in vacuo. The residue
was puri®ed by silica gel column chromatography
(dichloromethane:methanol=40:1) to give (R)-12 (3.86 g,
(R)-N-{2-[(1-(Benzofurane-2-yl))-pentyl]}propionamide
(R)-4. (R)-3 (0.47 g, 2.31 mmol) and triethylamine (0.48
mL, 3.44 mmol) were dissolved in dichloromethane
(4.00 mL). To the solution was added propionyl chlo-
ride (0.43 g, 4.60 mmol) and the mixture was stirred at
room temperature for 4 h, and concentrated in vacuo.
The residue was puri®ed by silica gel column chroma-
tography (n-hexane:dichloromethane=40:1) to give (R)-
4 (0.49 g, 82%) as colorless needles: mp 84±85 ꢀC (from
94%) as colorless oil: [a]2D0 +20ꢀ (c 1.3, methanol); H
1
NMR (CDCl3) 0.92 (t, J=7.1 Hz, 3H), 1.35±1.75 (m, 4H),
3.21 (s, 1H), 3.78 (s, 3H), 4.70±4.80 (m, 1H), 5.00±5.15 (m,
2H), 5.40±5.50 (m, 1H), 7.25±7.34 (m, 5H); IR(neat) 3300,
2955, 1720, 1660, 1520 cmÀ1; MS 295(M++1), 234, 206,
187, 162, 110, HRMS (EI) m/z calcd for C15H22N2O4
(M+H)+ 295.1658; found 295.1617.
diethyl ether); [a]D20 À21ꢀ (c 1.0, methanol); H NMR
1
(CDCl3) 0.91 (t, J=6.7 Hz, 3H), 1.15 (t, J=7.7 Hz, 3H),
1.40±1.55 (m, 4H), 2.19 (q, J=7.7 Hz, 2H), 2.80±3.10
(m, 2H), 4.32 (m, 1H), 5.43 (m, 1H), 6.47 (s, 1H), 7.10±
7.40 (m, 2H),7.40-7.52 (m, 2H); IR(KBr) 3295, 1640,
1605, 1540 cmÀ1; MS 260(M++1), 202, 186, 160, 144,
128,103; HRMS (EI) m/z calcd for C16H20NO2 (M-
H)+258.1494; found 258.1460
(R)-1-(Benzofuran-2-yl)-2-benzyloxycarbonylamino-1-
pentanone (R)-14. To a À35 ꢀC solution of benzofuran
(2.64 g, 25.4 mmol) in tetrahydrofuran (90 mL) was
added dropwise n-butyllithium (1.54 M in hexane, 33.0
mL, 50.8 mmol) under argon atomosphere, and the
mixture was stirred at À30 to À25 ꢀC for 10 min and
then re¯uxed for 30 min. To the solution was added
quickly (R)-13 (3.00 g, 10.2 mmol) in tetrahydrofuran
(36 mL) within 1 min, and the mixture was stirried at
À30 ꢀC for 2 h. The reaction mixture was poured into
saturated NH4Cl. The aqueous phase was extracted
with ethyl acetate. The organic layer was washed with
saturated NaHCO3, dried over anhydrous sodium sul-
fate, and concentrated in vacuo. The residue was pur-
i®ed by silica gel column chromatography (n-
hexane:dichloromethane=1:1) to give (R)-14 (1.63 g,
46%) as colorless needles; mp 91±92 ꢀC (from diethyl
(R)-1-(Benzofuran-2-yl)-2-propylaminopentane
(R)-1
hydrochloride. A solution of (R)-4 (1.76 g, 6.79 mmol)
in diethyl ether (20 mL) was added to a suspension of
lithium aluminum hydride (1.03 g, 27.1 mmol) in diethyl
ether (20 mL). The mixture was stirred at 0 ꢀC for 30
min and then re¯uxed for 2 h with stirring. After being
cooled, sodium ¯uoride (4.56 g, 10.9 mmol) was added
to the solution at 0 ꢀC, and the mixture was stirred at
room temperature for 1 h. The reaction mixture was
diluted with water (1.47 mL), and washed with dichlor-
omethane:ethanol (95:5 mL), and ethyl acetate:ethanol
(95:5 mL). The combined ®ltrates were concentrated in
vacuo. The residue was puri®ed by silica gel column
chromatography (dichloromethane:methanol=10:1) to
give (R)-1 (1.40 g, 84%), which was treated with HCl in
diethyl ether to give (R)-1 hydrochloride (1.24 g, 64%).
ether); [a]2D0 À48ꢀ (c 1.0, methanol); H NMR (CDCl3)
1
0.94 (t, J=7.1 Hz, 3H), 1.40±2.10 (m, 4H), 5.12 (s, 2H),
5.26±5.30 (m, 1H), 5.60±5.64 (m,1H), 7.25±7.36 (m, 5H),
7.48-7.75 (m, 5H); IR(KBr) 3320, 1685, 1665, 1610,
1530 cmÀ1, MS 352 (M++1), 308, 244, 207, 173, 145;
HRMS (EI) m/z calcd for C21H21NO4 (M+) 351.1470;
found 351.1487.
Crystallographic studies. Crystal of (À)-1ꢁ HCl was
grown from ethanol and diethyl ether by slow evapora-
tion at room temperature. A summary of the crystal-
lographic data is given in Table 1. The unit-cell

T. Oka et al. / Bioorg. Med. Chem. 9 (2001) 1213±1219
1219
dimensions were determined by a least-squares ®t of 2y
angles for 25 re¯ections, measured by graphite-mono-
chromated Cu-Ka radiation (l=1.5418 A) on an auto-
mated Rigaku AFC-5 di€ractometer. Intensity data
were collected in a o-2y scan mode using the same dif-
fractometer; the back-grounds were countered for 5 s at
both extreams of each re¯ection peak. Four standard
re¯ections were monitored for every 100 re¯ection
intervals throughout the data collection, showing a ran-
dom variation of Æ2% with no signi®cant trends. The
observed intensities were corrected for the Lorentz and
polarization e€ects, but not for the absorption e€ect.
(b) Parkinson Study Group New. Engl. J. Med. 1989, 321,
1364.
8. Sano, M.; Ernesto, C.; Thomas, R. G.; Klauber, M. R.;
Schafer, K.; Grundman, M.; Woodbury, P.; Growdon, J.;
Cotman, C. W.; Pfei€er, E.; Schneider, L. S.; Thal, L. J. New
Engl. J. Med. 1997, 336, 1216.
9. Knoll, J. Pharmacol. Toxicol. 1998, 82, 57.
10. (a) Knoll, J.; Yoneda, F.; Knoll, B.; Ohde, H.; Miklya, I.
British J. Pharm. 1999, 128, 1723. (b) Yoneda, F.; Moto, T.;
Sakae, M.; Ohde, H.; Knoll, B.; Miklya, I.; Knoll, J. Bioorg.
Med. Chem. 2001, 9, in press.
11. Gschwend, H. W.; Rodriguez, H. R. Org. React. (N.Y.)
1972, 26, 1.
12. (a) Oppolzer, W.; Flaskamp, E. Hel. Chim. Acta 1977, 22,
204. (b) Farmer, J. J.; Attygalle, A. B.; Smedley, S. R.; Eisner,
T.; Meinwald, J. Tetrahedron Lett. 1997, 38, 2787.
13. Edwards, P. D.; Wolanin, D. J.; Andisk, D. W.; Davis,
M. W. J. Med. Chem. 1995, 38, 76.
14. Sun, G.; Slavica, M.; Uretsky, N. J.; Wallace, L. J.;
Shams, G.; Weinstein, D. M.; Miller, J. C.; Millar, D. D. J.
Med. Chem. 1998, 41, 1034.
The structure of (À)-1ꢁ HCl was solved by the direct
method using the SHELXS 97 program19 and re®ned
by the full-matrix least squares method with aniso-
tropic thermal parameters. The atomic factors and
terms of anomalous dispersion corrections were taken
from ref 20.
15. Conditions for analytical chromatography of 1: column,
CHIRALPAK AD-RH (0.46 cmÂ1.5 cm); eluent, 20 mM
phosphate bu€er (pH 8.0):acetonitrile=3:2; ¯ow rate, 1.0 mL/
min; detection, UV 249 nm; retention times 35 (R) and 39 min
(S). The (R)-1ꢁ HCl obtained by two methods was in high
optical purity (>98% ee).
16. Dina, G. D.; Otto, M. J.; Treasurywala, A. M.; McKinlay,
M. A.; Oglesby, R. C.; Maliski, E. G.; Rossmann, M. G.;
Smith, T. J. J. Med. Chem. 1988, 31, 540.
References and Notes
1. Knoll, J.; Miklya, I. Life Sci. 1995, 56, 611.
2. (a) Knoll, J. Pharmacol. Toxicol. 1994, 75, 65. (b) Knoll, J.
Biomed. & Pharmacother. 1995, 49, 187. (c) Knoll, J. Exp.
Gerontol 1997, 32, 539. (d) Knoll, J. Neurobiology 2000, 8, 179.
3. Knoll, J.; Magyar, K. Adv. Bioch. Psychopharmacol. 1972,
5, 393.
17. Davis, F. A.; Zhou, P.; Liang, C.-H; Reddy, R. E. Tetra-
hedron: Asymmetry 1995, 6, 1511.
4. Knoll, J.; Knoll, B.; Torok, Z.; Tima
Â
Â
r, J.; Yasar, S. Arch.
18. Izumiya, N.; Yamashita, T. J. Biochem. 1959, 46, 19.
19. Sheldrick, G. M., SHELXS 97. Programs for the Solution
È
int. Pharmacodyn. Ther. 1992, 316, 5.
È
5. Knoll, J. Mech. Ageing & Dev. 1988, 46, 237.
6. Tatton, W. G.; Grenwood, C. E. J. Neurosci. Res. 1991, 30,
666.
of Crystral Structure, University of Gottingen, Germany,
1997.
20. International Tables for X-ray Crystallography, Vol. C,
Kluwer Academic Publishers, 1992.
È
7. (a) Terud, J. W.; Langston, J. W. Science 1989, 245, 519.