Synthesis of 2,6-dimethyl-9-aryl-9-phosphabicyclo[3.3.1]nonanes: their application to asymmetric synthesis of chiral tetrahydroquinolines and relatives

Article abstract of DOI:10.1016/j.tet.2007.03.078

Synthesis of 2,6-dimethyl-9-aryl-9-phosphabicyclo[3.3.1]nonanes from 1,5-cyclooctadiene and their application to asymmetric cyclization leading to chiral tetrahydroquinolines and relatives through palladium-catalyzed allylic alkylation are described.

Full text of DOI:10.1016/j.tet.2007.03.078

Tetrahedron 63 (2007) 6170–6181
Synthesis of 2,6-dimethyl-9-aryl-9-phosphabicyclo[3.3.1]nonanes:
their application to asymmetric synthesis of chiral
tetrahydroquinolines and relatives
Osamu Hara,b Tomoaki Koshizawa,a Kazuishi Makino,a Iyo Kunimune,a
Atsushi Namikia and Yasumasa Hamadaa,
*
aGraduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
bFaculty of Pharmacy, Meijo University, 150 Yagotoyama Tempaku-ku, Nagoya 460-8503, Japan
Received 25 January 2007; revised 13 March 2007; accepted 13 March 2007
Available online 16 March 2007
Dedicated to the memory of the Late Professor Yoshihiko Ito
Abstract—Synthesis of 2,6-dimethyl-9-aryl-9-phosphabicyclo[3.3.1]nonanes from 1,5-cyclooctadiene and their application to asymmetric
cyclization leading to chiral tetrahydroquinolines and relatives through palladium-catalyzed allylic alkylation are described.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Chiral phosphines have proved to play a crucial role as chiral
ligands for transition-metal catalyzed asymmetric synthesis
and their combinations with transition metals have been
shown to be especially useful and versatile catalysts for a va-
riety of enantioselective reactions, for example, asymmetric
hydrogenation, asymmetric allylic alkylation, asymmetric
hydrosilylation, asymmetric intramolecular Heck reaction,
and so on.1 Several years ago, we have developed a new class
of monodentate ligands, (1R,2S,5R,6S)-2,6-dimethyl-9-
phenyl-9-phosphabicyclo[3.3.1]nonane and its enantiomer
((R)- and (S)-9-PBNs, 1),2 as shown in Figure 1 and these
phosphines in combination with palladium are efficient cat-
alysts for the formation of carbon–carbon, carbon–nitrogen,
and carbon–oxygen bonds, and asymmetric cyclization
through asymmetric allylic alkylation reaction.3,4 In the
course of our studies on development of chiral auxiliaries
with the 2,6-dimethyl-9-phosphabicyclo[3.3.1]nonane skel-
eton, we have been interested in replacement of the
P-substituent on the 9-PBN for improving their enantio-
discriminating ability. In this article, we describe here
the full detail of preparation of 9-PBNs and new monoden-
tate phosphines, 2,6-dimethyl-9-(1-naphthyl)-9-phosphabi-
cyclo[3.3.1]nonanes ((S)-and (R)-9-NapBNs, 2)5 and their
application to asymmetric cyclization leading to chiral
P
P
(S)-(-)-9-NapBN (2)
(S)-(+)-9-PBN (1)
Figure 1.
tetrahydroquinolines and relatives through palladium-
catalyzed allylic alkylation. Although we have already
examined this approach using a racemic substrate,3c,d there
is, to date, no enantioselective approach through palla-
dium-catalyzed allylic alkylation leading to the tetrahydro-
quinolines. Chiral tetrahydroquinolines are synthetically
important targets as a result of their presence in natural prod-
ucts, pharmaceuticals, and other bioactive molecules. For
example, martinelline and martinellic acid, novel bradykinin
antagonists, are natural products with a unique pyrrolo[3,2-
c]quinoline ring.6,7 Their important properties and useful-
ness have prompted efforts for their efficient synthesis.8
2. Results and discussion
2.1. Design and synthesis of monodentate phosphines,
2,6-dimethyl-9-aryl-9-phosphabicyclo[3.3.1]nonanes
Keywords: Asymmetric cyclization; Palladium-catalyzed allylic amination;
Chiral phosphine; Tetrahydroquinoline.
In designing a monodentate phosphine bearing an inherent
lack of chelating ability, we envisaged that restriction of
* Corresponding author. Tel./fax: +81 43 290 2987; e-mail: hamada@p.
chiba-u.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.078

O. Hara et al. / Tetrahedron 63 (2007) 6170–6181
6171
Table 1. Double substitution reaction of 6
free rotation around the bond between the metal and the
phosphine in the catalyst might be a key element and
enhance the enantiodiscriminating ability. Thus, we used
the 1,3-diaxial interaction on the six-membered ring for
this purpose as shown in Figure 2. For an easy preparation
and prevention of flipping at the six-membered ring, the
new skeleton, 2,6-dimethyl-9-aryl-9-phosphabicyclo[3.3.1]-
nonane, for the monodentate phosphines was designed,
which would be efficiently constructed from 1,5-dimethyl-
1,5-cyclooctadiene through hydroboration.
Entry Phosphide anion
Yield (%)
of (S)-9
1
2
PhPH2 (7), n-BuLi, THF, 0 ꢀC; then BH3$THF
PhPH2, K–Na alloy, PhCH3/dioxane, 23 ꢀC; then
BH3$THF
0 (dec)
0–60
3
4
PhPH2$BH3 (8), KOtBu, BnEt3NCl, PhCH3,
ꢁ10 ꢀC, 1 h; 23 ꢀC, 14 h
62
1-NaphthylPH2$BH3 (10), KOtBu, BnEt3NCl,
PhCH3, 23 ꢀC, 18 h
52a
a
Yield of (S)-11.
L
Ar
(75/25 weight ratio), however, proceeded after treatment
with the borane/tetrahydrofuran complex for purification
to furnish the desired (1R,2S,5R,6S)-2,6-dimethyl-9-phenyl-
9-phosphabicyclo[3.3.1]nonane borane complex ((R)-9-
PBN$BH3, 9) as air-stable crystals. After several trials, the
above double substitution reaction, however, was found to
bear the problem of reproducibility. In our efforts to over-
come this problem, we were pleased to find a new reliable
method using the phosphine borane–quaternary ammonium
salt base rather than the phosphide dianion. The phosphine
borane complex 8 was prepared by mixing 7 with borane/
THF complex solution in toluene and directly used for the
next reaction. The double substitution reaction of (R)-ditosyl-
ate 6 (1 equiv) with PhPH2$BH3 (8, 1.1 equiv) was carried
out in the presence of potassium tert-butoxide (3 equiv)
and benzyltriethylammonium chloride (0.2 equiv) in toluene
at 23 ꢀC for 14 h to afford (S)-9-PBN$BH3 (9) in 62% yield
as nice crystallines. The required free phosphine (S)-1 is
quantitatively regenerated by the reaction of phosphine
borane 9 with 1,4-diazabicyclo[2.2.2]octane (DABCO,
1 equiv)12 and can be conveniently used as its hexane solu-
tion. The stereochemical integrity of the final phosphine 1
and lack of racemization through the substitution reaction
were unequivocally confirmed using chiral HPLC analysis.
The antipodal (R)-9-PBN (1) was similarly prepared from
the (R)-diol. In addition, the absolute configuration of thus
obtained (R)-9 was unambiguously determined by the X-
ray crystallography of its borane complex,2 which supports
the above results of the enzymatic resolution and the modi-
fied Mosher method. The synthesis of (S)-9-NapBN (2) was
also performed by using the above method. The required
1-naphthylphosphine was prepared according to the known
method.13 The phosphine borane 10 was prepared by mixing
1-naphthylphosphine with borane/dimethylsulfide complex in
toluene and directly used for the next substitution reaction.
L
M
P
L
P
Ar = Ph: (S)-(+)-9-PBN (1)
Ar = 1-naphthyl: (S)-(-)-9-NapBN (2)
Figure 2.
The preparation of optically active 1 was carried out from
commercially available 1,5-dimethyl-1,5-cyclooctadiene
(3) through enzymatic resolution as shown in Scheme 1.
Hydroboration of 3 with sodium borohydride and boron tri-
fluoride etherate gave (rac)-diol 4 in moderate yield.9 Subse-
quent resolution10 of 4 with lipase My was performed in the
presence of an excess amount of lauric acid in heptane at
50 ꢀC. The reaction was quite sluggish even at 50 ꢀC but
was found to afford efficiently (S)-diol 4 and (R)-dilauroyl
ester 5 with high optical purities. Further purification of
the (S)-diol 4 was achieved by recrystallization and its opti-
cal purity was confirmed to be 100% ee after conversion
to the diMTPA ester by the NMR analysis. The (R)-diester
5 was hydrolyzed with potassium carbonate in methanol
to provide after recrystallization the enantiomerically pure
(R)-4. The absolute stereochemistry of each diol was con-
firmed by both the results of the lipase My-catalyzed esteri-
fication and the modified Mosher method.11 Tosylation of
(S)-4 gave the labile ditosylate 6. The double substitution re-
action of the freshly prepared 6 was first problematic as
shown in Table 1. The yield of the product was dependent
on the counter cation used. The dilithium phenylphosphide
generated from phenylphosphine (7) and n-butyl lithium
caused complete decomposition of the substrate. Fortu-
nately, the dipotassium phenylphosphide in situ generated
from phenylphosphine (7) and potassium/sodium alloy
OH
OR
OH
b
a
+
HO
RO
HO
3
(rac)-4
(S)-4
5: R = lauroyl
(R)-4: R = H
c
Ar
Ar
P
H3B
ArP2-
see Table 1
OTs
P
d
e
(R)-4
TsO
(S)-1: Ar = Ph
(S)-2: Ar = 1-naphthyl
(R)-6
(S)-9: Ar = Ph
(S)-11: Ar = 1-naphthyl
Scheme 1. Preparation of 6-dimethyl-9-aryl-9-phosphabicyclo[3.3.1]nonane. Reagents and conditions: (a) NaBH4, BF3$OEt2, THF; then NaOH, H2O2; (b)
lipase My, lauric acid, heptane; (c) K2CO3, MeOH; (d) p-TsCl, pyridine; (e) DABCO, THF.

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O. Hara et al. / Tetrahedron 63 (2007) 6170–6181
The double substitution reaction of (R)-ditosylate 6
(1.07 equiv) with the 1-naphthylphosphine borane complex
10 (1 equiv) was carried out in the presence of potassium
tert-butoxide (3 equiv) and benzyltriethylammonium chlo-
ride (0.18 equiv) in toluene at 23 ꢀC for 18 h to afford (S)-
9-NapBN$BH3 (11) in 52% yield as nice crystallines. The
free phosphine (S)-2 was obtained by treatment of 11 with
DABCO in refluxing tetrahydrofuran for 2 h in 83% yield
as crystallines.
tosylation of the amino function. The other substrates 22b
and 22c were obtained by the use of o- and p-nitrobenzene-
sulfonyl chloride, respectively. The cyclization reaction was
carried out by using the previously developed conditions,2
bis(dibenzylideneacetone)palladium (Pd(dba)2, 2 mol %)
or allyl palladium chloride dimer ([(h3-C3H5)PdCl]2,
5 mol %) and our phosphine in the presence of bis(trimethyl-
silyl)acetamide (BSA, 3 equiv) and lithium acetate (1 equiv)
in tetrahydrofuran at 23 ꢀC for 20 h (Table 2). The initial ex-
periment using the N-tosyl substrate 22a and (S)-9-PBN (1)
was found to afford tetrahydroquinoline 36a in 68% yield
with 72% ee. The enantiomeric excess was determined by
HPLC analysis. With this encouraging result in hand, we ex-
amined the bulkiness of the N-protecting group and the acid-
ity of the sulfonamide (entries 2 and 3), which proved no or
little effects. The effect of the ligand was next investigated
by using (S)-NapBN (2) and in the case of the N-tosyl sub-
strate 22a the corresponding product was obtained in 48%
yield with 92% ee but the reaction was incomplete with re-
covery of the substrate (28% yield). In order to overcome
the low conversion, 5 mol % Pd(dba)2 and 10 mol % phos-
phine were applied but the yield was still moderate (entry
5). The reaction using the N-p-nitrobenzenesulfonamide
substrate 22c with hope of improving the chemical yield pro-
ceeded with 94% ee but the reaction was still incomplete
(entry 6). Use of allyl palladium chloride dimer somewhat
improved the chemical yield and the enantioselectivity (en-
try 7). On the contrary, asymmetric allylic substitution reac-
tions using the typical ligands, (R)-BINAP (39) and Trost’s
ligand 40, under the similar condition to that in entry 7
2.2. Asymmetric cyclization through allylic substitution
reaction
To explore the potential of 9-PBN and new 9-NapBN, we
selected asymmetric cyclization14 of o-substituted aniline
sulfonamides 22a–c leading to chiral tetrahydroquinolines
36a–c as an initial test reaction. The results are summarized
in Table 2. The substrates 22a–c were easily prepared from
commercially available o-iodoaniline (12) in 10 steps as
shown in Scheme 2. Thus, Sonogashira coupling reaction
of 12 with the propargyl alcohol derivative gave the three-
carbon homologated 13, which was subjected to a four-step
standard manipulation, hydrogenation of 13, N-protection
with di-tert-butyl dicarbonate, removal of the tetrahydro-
pyranyl group, and oxidation of the resulting alcohol 16, to
afford cyclized hemiaminal 17 in good yield. Wittig olefina-
tion of 17 proceeded selectively to produce a,b-unsaturated
ester 18, which was converted into substrate 22a by a four-
step sequence, reduction of 18, acetylation of the resulting
alcohol 19, deprotection of tert-butoxycarbonyl group, and
Table 2. Asymmetric cyclization to the tetrahydroquinoline derivatives
Pd (2 mol %)
phosphine (4 mol %)
OAc
n
n
BSA (3 equiv)
LiOAc (1 equiv)
THF
N
R
NHR
22a: n = 1, R = Ts
36a: n = 1, R = Ts
rt, 20 h
22b: n = 1, R = o-NO2PhSO2
22c: n = 1, R = p-NO2PhSO2
32: n = 2, R = Ts
36b: n = 1, R = o-NO2PhSO2
-
-
36c: n = 1, R = p-NO2PhSO2
37: n = 2, R = Ts
-
-
35: n = 0, R = Ts
38: n = 0, R = Ts
Entry
Substrate
Pd
Phosphine
Yielda (%)
ee (%)
1
2
3
22a
22b
22c
22a
22a
22c
22a
22a
22a
32
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
(S)-9-PBN
(S)-9-PBN
(S)-9-PBN
(S)-9-NapBN
(S)-9-NapBN
(S)-9-NapBN
(R)-9-NapBN
(R)-BINAP 39
68 (26)
51 (26)
86 (8)
48 (28)
55 (16)
28 (30)
61 (14)
60 (14)
72 (R)
56 (R)
65 (R)
92 (R)
92 (R)
94 (R)
94 (S)
0
4
5b
6
Pd(dba)2
7c
8d
9d
10c
11c
[(h3-C3H5)PdCl]2
[(h3-C3H5)PdCl]2
[(h3-C3H5)PdCl]2
[(h3-C3H5)PdCl]2
[(h3-C3H5)PdCl]2
Trost’s ligand 40
(R)-9-NapBN
(S)-9-NapBN
48 (35)
29
Trace
17
55
62
35
a
Isolated Yield. The value in parentheses is the recovery yield of the starting material.
Pd(dba)2 of 5 mol % was used.
[(allyl)PdCl]2 of 5 mol % and (R)-9-NapBN of 20 mol % were used.
b
c
d
The reaction was carried out by using 5 mol % [(h3-C3H5)PdCl]2 and 10 mol % ligand for 36 h.
O
O
PPh2
NH HN
PPh2
PPh2 Ph2P
Trost ligand 40
(R)-BINAP 39

O. Hara et al. / Tetrahedron 63 (2007) 6170–6181
6173
OTHP
n
b
OR1
n
NHR2
14: n = 2, R1 = THP, R2 = H
15: n = 2, R1 = THP, R2 = Boc
16: n = 2, R1 = H, R2 = Boc
24: n = 3, R1 = THP, R2 = H
25: n = 3, R1 = THP, R2 = Boc
I
a
c
d
NH2
NH2
c
12
13: n=1
23: n=2
d
26: n = 3, R1 = H, R2 = Boc
H
CO2Et
n
e
f
or
O
N
OH
NHBoc
NHBoc
Boc
27
18: n=1
28: n=2
17
19: n = 1, R1 = H, R2 = Boc
OR1
g
h
i
20: n = 1, R1 = Ac, R2 = Boc
n
NHR2
21: n = 1, R1 = Ac, R2 = H
22a: n = 1, R1 = Ac, R2 = Ts
j
22b: n = 1, R1 = Ac, R2 = o-NO2PhSO2
-
22c: n = 1, R1 = Ac, R2 = p-NO2PhSO2
-
29: n = 2, R1 = H, R2 = Boc
h
i
30: n = 2, R1 = Ac, R2 = Boc
j
31: n = 2, R1 = Ac, R2 = H
32: n = 2, R1 = Ac, R2 = Ts
I
Cl
OAc
k
l
NHTs
NHTs
34
NHTs
33
35
Scheme 2. Preparation of the substrates for asymmetric cyclization. Reagents and conditions: (a) tetrahydro-2-(2-propynyloxy)-2H-pyran, (Ph3P)2PdCl2, CuI,
Et2NH for 13; tetrahydro-2-(but-3-ynyloxy)-2H-pyran, (Ph3P)2PdCl2, CuI, Et2NH for 23; (b) H2, 5% Pd/C, MeOH; (c) Boc2O, Et3N, THF; (d) PPTS, EtOH; (e)
Swern oxidation; (f) Ph3P]CHCO2Et, PhCH3; (g) DIBAL, PhCH3; (h) Ac2O, pyridine; (i) CF3CO2H; (j) p-TsCl and pyridine for 22a and 32; o-NsCl and
pyridine for 22b; p-NsCl and pyridine for 22c; (k) n-BuLi, 1,4-dichloro-2-butene; (l) KOAc, DMSO.
showed much lower enantioselectivities (entries 8 and 9),
which revealed the excellent features of our phosphines,
9-PBN and 9-NapBN. Other substrates leading to the benzo-
azepine 37 and indoline 38 were next investigated in this
asymmetric cyclization. The required substrate 32 for 37
was also prepared by using the similar method to that for
22a. The substrate 35 for 38 was prepared by direct coupling
of 1,4-dichloro-2-butene and the aryl lithium generated by
halogen/lithium exchange reaction from N-(o-iodophenyl)-
p-toluenesulfonamide (33) (Scheme 2). As depicted in
Scheme 3, the absolute configuration of the tetrahydroquino-
line 36a was established after conversion to the known tetra-
hydroquinolineacetic acid derivative 41. Thus, 36a with
24% ee ([a]2D6 ꢁ7.88 (c 1.21, CHCl3)) was hydroborated
with borane dimethylsulfide complex and the resulting alco-
hol was oxidized to the carboxylic acid with Jones’ reagent,
which was esterified with iodomethane and potassium hy-
drogen carbonate in dimethylformamide and N-deprotected
with magnesium in methanol to furnish 41 with 21% ee
([a]2D5 ꢁ22.6 (c 0.415, CHCl3)). The comparison with the
literature value15 has unambiguously established that the
tetrahydroquinoline 36a has the R configuration at the C2
position.
Although the reaction mechanism of the asymmetric induc-
tion with a high level of enantioselectivity through intramo-
lecular allylic alkylation is not clear at present, we speculate
that the reaction proceeds via the allyl/palladium complex
avoiding the steric interaction with the methyl and the
P-naphthyl substituents at the (S)-phosphine ligand to afford
the (R)-product as shown in Figure 3.
L
Pd
P
RN
Figure 3.
1. BH3•SMe2, then NaOH, H2O2, 48 %
2. Jones oxidation
3. MeI, KHCO3, DMF, 62 % in two steps
4. Mg, MeOH, 74 %
CO2Me
N
N
H
Ts
36a
41
[α]D26-7.88 (c 1.21, CHCl3)
24 %ee (by HPLC)
[α]D25-22.6 (c 0.415, CHCl3)
21 %ee
Scheme 3.

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O. Hara et al. / Tetrahedron 63 (2007) 6170–6181
3. Conclusion
recrystallized from 90% aqueous MeOH to give (R)-5
(66.5 g, 43%) as colorless fine crystals. The mixture of the
enzyme and the unreacted (S)-diol 4 was washed with hot
benzene/THF (1/1) (230 mlꢂ2) and the filtrate was concen-
trated in vacuo. The resulting crude (S)-diol 4 was recrystal-
lized from dichloroethane to give (S)-diol 4 (19.7 g, 40%) as
colorless needles. Compound (S)-4: mp 138 ꢀC; [a]D20
+12.84 (c 1.05, MeOH); IR (KBr): 3324, 2953, 1040,
We have succeeded in the development of a new class
of chiral monodentate phosphines, 2,6-dimethyl-9-aryl-9-
phosphabicyclo[3.3.1]nonanes (9-PBNs and 9-NapBNs).
Their application to asymmetric cyclization through intra-
molecular palladium-catalyzed allylic alkylation demon-
strates a potential of these phosphines.
1
1011 cmꢁ1; H NMR (CDCl3/DMSO-d6, 60 MHz): d 0.96
(d, J¼6 Hz, 6H), 1.14–2.07 (m, 10H), 2.87–3.38 (m, 2H),
4.04 (d, J¼5 Hz, 2H); Anal. Calcd for C10H20O2: C, 69.72;
H, 11.70. Found: C, 69.49; H, 11.79. Compound (R)-5: mp
46–47 ꢀC (MeOH); [a]D20 ꢁ31.01 (c 1.01, CHCl3); IR (KBr):
2915, 1728, 1175 cmꢁ1; 1H NMR (CDCl3, 60 MHz): d 0.87
(t, J¼7 Hz, 6H), 0.93 (d, J¼7 Hz, 6H), 1.05–2.02 (m, 46H),
2.10–2.44 (m, 4H), 4.41–4.82 (br, 2H). Anal. Calcd for
C34H64O4: C, 76.06; H, 12.02. Found: C, 76.14; H, 12.11.
4. Experimental
4.1. General
Melting points were measured with a SIBATA NEL-270
melting point apparatus and are uncorrected. Optical rota-
tions were measured on a JASCO P-1020 polarimeter with
a sodium lamp (589 nm). Infrared spectra were recorded
on a SHIMADZU FTIR-8100 JASCO FT/IR-230 spectro-
meter. NMR spectra were recorded on JEOL JNM-GSX-400A
and JNM-ECP-400 spectrometers with tetramethylsilane as
an internal standard, unless otherwise indicated. Mass spec-
tra were measured on a JMX-AX-500 spectrometer. Column
chromatography was performed with silica gel BW-820MH
or BW-200 (Fuji Davison Co.). HPLC analyses were carried
out on the chiral column indicated in each experiment. All
commercially available reagents were used as received.
A mixture of (R)-5 (30.39 g, 57 mmol) and K2CO3 (20 g,
145 mmol) in MeOH (500 ml) was stirred at room tempera-
ture for 44 h. The reaction mixture was concentrated in
vacuo and the resulting white solids were washed thoroughly
with ether. The filtrate was concentrated in vacuo and the
resulting crude (R)-diol 4 was washed with n-hexane and
recrystallized from dichloroethane to give pure (R)-diol 4
(6.76 g, 69%) as colorless needles: mp 138–139 ꢀC; [a]D20
ꢁ12.75 (c 1.04, MeOH); IR (KBr): 3320 (–OH), 2953, 1040,
1
1011 cmꢁ1; H NMR (CDCl3/DMSO-d6, 60 MHz): d 0.98
4.2. Synthesis of 2,6-dimethyl-9-aryl-9-phosphabicyclo-
[3.3.1]nonanes
(d, J¼6 Hz, 6H,), 1.16–2.01 (m, 10H), 2.89–3.41 (m, 2H),
3.86 (d, J¼5 Hz, 2H). Anal. Calcd for C10H20O2: C, 69.72;
H, 11.70. Found: C, 69.54; H, 11.51.
4.2.1. 2,6-Dimethyl-1,5-cyclooctanediol (4). To a stirred
mixture of NaBH4 (5.08 g, 0.13 mol) and 1,5-dimethyl-1,5-
cyclooctadiene (3) (23.2 g, 0.17 mol) in THF (110 ml)
cooled to 0 ꢀC was added dropwise boron trifluoride etherate
(25.5 g, 0.18 mol) over 1 h. After stirring the mixture at room
temperature for 1 h and at reflux for 1 h, the reaction mixture
was cooled to room temperature and quenched by dropwise
addition of ethanol (10.6 ml, 0.18 mol). Aqueous NaOH
(3 M, 60 ml) and 30% aqueous H2O2 (36 ml, 0.36 mol)
were added dropwise, maintaining the internal temperature
below 45 ꢀC. The mixture was stirred at 40–50 ꢀC for 1 h,
cooled to room temperature, saturated with K2CO3, and ex-
tracted with ethyl acetate (200 mlꢂ2). The combined organic
layers were washed with saturated brine (100 mlꢂ2), dried
over MgSO4, and concentrated in vacuo. The residue was
crystallized from ethyl acetate/n-hexane and the resulting
crude diol 4 was recrystallized from 1,2-dichloroethane to
give pure diol 4 (16.02 g, 55%) as colorless needles: mp
109.5–111 ꢀC; IR (KBr): 3322, 2953, 1040, 1011 cmꢁ1; 1H
NMR (CDCl3/DMSO-d6, 60 MHz): d 0.98 (d, J¼6 Hz, 6H),
1.17–2.07(m, 10H), 2.96–3.41(m, 2H), 3.58(d, J¼5 Hz, 2H).
4.2.3. Determination of optical purities of the diols 4. The
(S)- and (R)-diols 4 were converted to the corresponding
(S)-MTPA esters and their optical purities were determined
by comparison of their 1H NMR spectra.
4.2.3.1. (S)-MTPA ester of the (S)-diol 4. To a solution
of the above (S)-diol 4 (7 mg, 0.041 mmol) and DMAP
(50 mg, 0.41 mmol) in ether (1 ml) was added a 0.14 M so-
lution of MTPACl (prepared by the reaction of MTPA with
thionyl chloride) in CH2Cl2 (1 ml). The mixture was stirred
at room temperature for 0.5 h. After dilution with ether
(50 ml), the mixture was washed with 1 M aqueous KHSO4,
water, saturated aqueous NaHCO3, water, and saturated
brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified on a silica gel plate (E. Merck Art.
5715) to give 20 mg (78%) of the (S)-MTPA ester as a color-
less viscous oil; IR: 1744, 1272, 1169, 1123, 1022, 995,
1
720 cmꢁ1; H NMR (CDCl3): d 0.80 (d, J¼6.6 Hz, 6H,),
1.40–1.48 (m, 2H), 1.75–1.98 (m, 8H), 3.552 (d, J¼
1.1 Hz, 6H, O–CH3), 4.78–4.83 (m, 2H), 7.37–7.41 (m, 6H),
7.52–7.55 (m, 4H). The 1H NMR spectrum showed the ab-
sence of the corresponding isomer derived from the (R)-diol.
4.2.2. Resolution of 2,6-dimethyl-1,5-cyclooctanediol (4).
A mixture of the (rac)-diol 4 (50 g, 0.29 mol), lauric acid
(116 g, 0.6 mol), and lipase My (14.8 g) in heptane
(290 ml) was stirred at 50 ꢀC for 8 days. The reaction
mixture was cooled to room temperature, then the enzyme
and the unreacted (S)-diol 4 were filtered off. The filtrate
was concentrated in vacuo and the residue was chromato-
graphed on silica gel (n-hexane to n-hexane/ethyl acetate¼
9/1) to give a mixture of (R)-1,5-bis(lauroyloxy)-2,6-di-
methylcyclooctane (5) and lauric acid. The mixture was
4.2.3.2. (S)-MTPA ester of the (R)-diol 4. Prepared from
the above (R)-diol 4 (7 mg, 0.041 mmol) as described above;
IR: 1744, 1271, 1171, 1123, 1022, 994, 720 cmꢁ1; 1H NMR
(CDCl3): d 0.91 (d, J¼6.8 Hz, 6H), 1.33–1.42 (m, 2H), 1.65–
1.97 (m, 8H), 3.527 (d, J¼1.1 Hz, 6H, O–CH3), 4.79–4.84
1
(m, 2H), 7.37–7.42 (m, 6H), 7.51–7.53 (m, 4H). The H
NMR spectrum showed the absence of the corresponding
isomer derived from the (S)-diol.

O. Hara et al. / Tetrahedron 63 (2007) 6170–6181
6175
4.2.4. (1R,2R,5R,6R)-1,5-Bis(p-toluenesulfonyloxy)-2,6-
dimethylcyclooctane (6). A mixture of the (R)-diol 4
(3.46 g, 20 mmol) and p-toluenesulfonyl chloride (15.3 g,
80 mmol) in pyridine (20 ml) was stirred at 0 ꢀC for 21 h,
then H2O (10 ml) was added and the mixture was stirred at
5 ꢀC for 1 h. The mixture was diluted with CH2Cl2/ether
(1/2, 200 ml) and the organic layer was washed with 1 M
KHSO4, water, saturated aqueous NaHCO3, water, and satu-
rated brine, dried over MgSO4, and concentrated in vacuo.
The residue was triturated with n-hexane/Et2O and the re-
sulting white solid was filtered, washed with n-hexane, and
dried in vacuo (room temperature, 1 h) to give (R)-6
(9.05 g, 94%) as unstable colorless solids. The analytical
sample was recrystallized from CH2Cl2/ether/n-hexane to
give pure (R)-6 as colorless flaky crystals: mp 91–92 ꢀC (de-
comp.); [a]1D8 ꢁ40.11 (c 1.83, CHCl3); IR (KBr): 1362,
4.2.7. (1R,2S,5R,6S)-2,6-Dimethyl-9-phenyl-9-phosphabi-
cyclo[3.3.1]nonane borane complex (9, (R)-9-PBN$BH3).
To a stirred suspension of ditosylate (S)-6 (2.41 g, 5 mmol),
benzyltriethylammonium chloride (228 mg, 1 mmol), and
potassium tert-butoxide (1.69 g, 15 mmol) in toluene
(40 ml) at ꢁ20 ꢀC was added a solution of phenylphosphine
borane complex 8 (prepared by mixing phenylphosphine
(2.5 M in toluene solution, 2.2 ml, 5.5 mmol) with a 1 M
solution of BH3/THF (6 ml, 6 mmol) at 0 ꢀC for 30 min).
The reaction mixture was stirred at ꢁ10 ꢀC for 1 h and at
room temperature for 18 h. Then the mixture was diluted
with ether and filtered through a Celite pad. The filtrate
was concentrated in vacuo and the residue was chromato-
graphed on silica gel (n-hexane/CH2Cl2¼3/2) to give the
(R)-9-PBN-borane complex 9 (811 mg, 62.4%, air stable)
as colorless crystals. Recrystallization from CH2Cl2/ether/
n-hexane gave colorless prisms: mp 166–170 ꢀC; [a]D21
+2.48 (c 1.26, CH2Cl2); IR (KBr): 2953, 2359 (B–H),
1
1171, 899, 668, 552 cmꢁ1; H NMR (CDCl3): d 0.79 (d,
J¼6.9 Hz, 6H), 1.21–1.29 (m, 2H), 1.67–1.91 (m, 8H), 2.43
(s, 6H), 4.26–4.33 (m, 2H), 7.33 (d, J¼8.6 Hz, 4H), 7.77 (d,
J¼8.3 Hz, 4H). Anal. Calcd for C24H32O6S2; C, 59.97; H,
6.71. Found: C, 59.89; H, 6.80. The ditosylate is labile under
room temperature and decomposes by long standing under
reduced pressure. The ditosylate should be briefly dried in
vacuo and stored in refrigerator.
1
2334 (BH), 1067, 704 cmꢁ1; H NMR (CDCl3): d 0.73–
0.86 (m, 1H), 0.88 (d, J¼7.3 Hz, 3H), 1.43 (d, J¼7.3 Hz,
3H), 1.49–2.68 (m, 11H), 7.37–7.53 (m, 5H). Anal. Calcd
for C16H26BP: C, 73.87; H, 10.07. Found: C, 73.90; H,
10.02.
4.2.8. (1R,2S,5R,6S)-2,6-Dimethyl-9-phenyl-9-phospha-
bicyclo[3.3.1]nonane (1, (R)-9-PBN). The (R)-9-PBN$BH3
(9, 260 mg, 1 mmol) and DABCO (112 mg, 1 mmol) were
dissolved in dry THF (2 ml) under an argon atmosphere.
The reaction mixture was refluxed for 2 h and the solvent
was evaporated. The residue was treated with dry hexane
(10 ml) and filtered through a cotton plug to give 0.1 M
(R)-9-PBN solution in n-hexane. (R)-9-PBN 1: [a]2D9 ꢁ30.7
4.2.5. (1S,2S,5S,6S)-1,5-Bis(p-toluenesulfonyloxy)-2,6-di-
methylcyclooctane (6). Compound (S)-6 (9.105 g, 95%)
was prepared from the (S)-diol 4 (3.45 g, 20 mmol) as de-
scribed above: mp 92–94 ꢀC (decomp.); [a]2D0 +40.02 (c
1.84, CHCl3); IR (KBr): 1362, 1171, 897, 668, 552 cmꢁ1
;
1H NMR (CDCl3): d 0.79 (d, J¼6.9 Hz, 6H), 1.21–1.29
(m, 2H), 1.67–1.91 (m, 8H), 2.44 (s, 6H), 4.23–4.30 (m,
2H), 7.33 (d, J¼8.6 Hz, 4H), 7.77 (d, J¼8.3 Hz, 4H).
Anal. Calcd for C24H32O6S2: C, 59.97; H, 6.71. Found: C,
59.81; H, 6.91.
1
(c 1, n-hexane); H NMR (CDCl3): d 0.86–0.95 (m, 1H),
0.88 (d, J¼7.1 Hz, 3H), 1.27 (m, 1H), 1.30 (d, J¼7.3 Hz,
3H), 1.48 (m, 1H), 1.6–2.38 (m, 8H), 2.49 (d, J¼10 Hz, 1H),
7.13 (m, 1H), 7.24 (m, 2H), 7.38 (m, 2H).
4.2.6. (1S,2R,5S,6R)-2,6-Dimethyl-9-phenyl-9-phosphabi-
cyclo[3.3.1]nonane borane complex (9, (S)-9-PBN$BH3).
Potassium (938 mg, 24 mmol) and sodium (235 mg,
10.2 mmol) were melted together in a Schlenk tube at
180 ꢀC under reduced pressure, cooled to room temperature,
and charged with argon gas. Then, dioxane (40 ml) followed
by a 3 M solution of phenylphosphine (7) in toluene (4 ml)
was added to the resulting suspension. The mixture was
stirred at room temperature for 10 h and at 95–100 ꢀC for
2 h, then cooled to room temperature. A solution of ditosyl-
ate (R)-6 (5.77 g, 12 mmol) in toluene (40 ml) was added
dropwise and stirred at room temperature for 2.5 h. The
mixture was filtered through a cotton plug under an argon
atmosphere and concentrated in vacuo to give crude phos-
phine (S)-7. The crude phosphine (S)-7 was treated with
a 1 M solution of BH3/THF in THF (12 ml). The mixture
was stirred at room temperature for 0.5 h and concentrated
in vacuo. The residue was purified by silica gel column chro-
matography (n-hexane/CH2Cl2¼3/2) to give the (S)-9-PBN-
borane complex 9 (1.37 g, 44%, air stable) as white solids,
then recrystallization from CH2Cl2/ether/n-hexane gave
colorless prisms: mp 165–169 ꢀC; [a]D21 ꢁ2.56 (c 1.26,
CH2Cl2); IR (KBr): 2953, 2359 (B–H), 2334 (B–H), 1067,
4.2.9. (1S,2R,5S,6R)-2,6-Dimethyl-9-(1-naphthyl)-9-
phosphabicyclo[3.3.1]nonane borane complex (11, (S)-
9-NapBN$BH3). To a stirred suspension of the ditosylate
(R)-6 (7.69 g, 16 mmol), benzyltriethylammonium chloride
(729 mg, 3.2 mmol), and potassium tert-butoxide (5.05 g,
45 mmol) in toluene (105 ml) at 5 ꢀC was added a solution
of 1-naphthylphosphine borane 10 (prepared by mixing
1-naphthylphosphine (1 M in toluene solution, 15 ml,
15 mmol) with BH3$SMe2 (1.65 ml, 16.5 mmol) at 23 ꢀC
for 2 h). The reaction mixture was stirred at 5 ꢀC for 1 h
and at 23 ꢀC for 18 h. Then the mixture was filtered through
a Celite pad and the filtrate was concentrated in vacuo. The
residue was chromatographed on silica gel (n-hexane/
CH2Cl2¼3/2) to give the (S)-9-NapBN borane complex 11
(2.42 g, 52%, air stable): 1H NMR (CDCl3): d 0.49 (d,
J¼7.02 Hz, 3H), 0.7–1.4 (m, 3H), 1.49 (d, J¼7.32 Hz,
3H), 1.55–1.9 (m, 5H), 2.0–2.2 (m, 2H), 2.25–2.45 (m, 2H),
2.65 (br s, 1H), 2.75–2.9 (m, 2H), 7.45–7.57 (m, 3H), 7.6–
7.7 (m, 1H), 7.8–7.95 (m, 2H), 8.1–8.35 (m, 1H). Anal.
Calcd for C20H28BP: C, 77.43; H, 9.10. Found: C, 77.51;
H, 9.14.
1
704 cmꢁ1; H NMR (CDCl3): d 0.81–0.99 (m, 1H), 0.95
4.2.10. (1S,2R,5S,6R)-2,6-Dimethyl-9-(1-naphthyl)-9-
phosphabicyclo[3.3.1]nonane (2, (S)-9-NapBN). The (S)-
9-NapBN$BH3 (11, 621 mg, 2 mmol) and DABCO
(246 mg, 2.2 mmol) were dissolved in dry THF (5 ml) under
(d, J¼7.3 Hz, 3H), 1.50 (d, J¼7.3 Hz, 3H), 1.55–2.77 (m,
10H), 7.43–7.60 (m, 5H). Anal. Calcd for C16H26BP: C,
73.87; H, 10.07. Found: C, 73.72; H, 9.95.

6176
O. Hara et al. / Tetrahedron 63 (2007) 6170–6181
an argon atmosphere. The reaction mixture was refluxed for
2 h and the solvent was evaporated. The residue was recrys-
tallized from methanol to give (S)-9-NapBN 2 (494 mg,
83%): mp 127–129 ꢀC; [a]D21 ꢁ248.8 (c 0.9, n-hexane); IR
(KBr): 3047, 2952, 2857, 1560, 1502, 1444, 1371, 796,
(m, 1H), 7.01–7.21 (m, 3H), 7.10 (br s, 1H), 7.74 (d, J¼
8.1 Hz, 1H); 13C NMR (CDCl3): d 19.7, 25.2, 26.7, 28.2,
30.0, 30.5, 62.5, 64.8, 79.8, 98.5, 22.6, 123.9, 126.4, 127.2,
128.1, 129.4, 131.6, 136.3, 153.5. HRMS (FAB, NBA) calcd
for C19H29NO4: 335.2097 (M+); found: 335.2085.
1
773 cmꢁ1; H NMR (CDCl3): d 0.47 (d, J¼6.71 Hz, 3H),
1.0–1.08 (m, 1H), 1.32–1.37 (m, 2H), 1.55–1.61 (m, 2H),
1.68–1.83 (m, 2H), 2.07–2.15 (m, 1H), 2.19–2.3 (m, 1H),
2.3–2.37 (m, 1H), 2.52–2.54 (m, 1H), 2.65 (br s, 2H), 7.36
(m, 1H), 7.5 (m, 2H), 7.2 (m, 1H), 7.71 (d, J¼8.24 Hz, 1H),
7.82 (d, J¼7.63 Hz, 1H), 8.27 (d, J¼7.94 Hz, 1H). Anal.
Calcd for C20H25P: C, 81.05; H, 8.50. Found: C, 81.20; H,
8.53.
4.3.4. 1-tert-Butoxycarbonylamino-2-(3-hydroxypropyl)-
benzene (16). To a stirred solution of 15 (67.7 mg,
0.202 mmol) in ethanol (2 ml) was added PPTS (5.03 mg,
0.020 mmol) and the reaction mixture was stirred at 55 ꢀC.
After 16 h, the reaction mixture was diluted with ethyl ace-
tate and washed with saturated aqueous NaHCO3, water, and
brine. The organic phase was dried over MgSO4 and concen-
trated in vacuo. The residue was purified by silica gel column
chromatography (n-hexane/ethyl acetate¼2/1) to give 16
(48.7 mg, 96%) as colorless crystals: mp 48–53 ꢀC (ethyl
4.3. Preparation of the substrates for asymmetric
cyclization
1
acetate/n-hexane); IR (KBr): 3311, 1697, 1523 cmꢁ1; H
4.3.1. 2-[3-(Tetrahydropyran-2-yloxy)prop-1-ynyl]phe-
nylamine (13). To a stirred solution of 2-iodoaniline (12,
1.02 g, 4.57 mmol) in Et2NH (9 ml) were added
(Ph3P)2PdCl2 (16 mg, 0.023 mmol), CuI (8.7 mg,
0.046 mmol), and tetrahydro-2-(2-propynyloxy)-2H-pyran
(640 mg, 4.57 mmol) under a nitrogen atmosphere and the
reaction mixture was stirred at room temperature. After
5 h, the volatile was removed in vacuo. The residue was di-
luted with ethyl acetate and washed with water. The organic
phase was dried over MgSO4 and concentrated in vacuo. The
residue was purified by silica gel column chromatography
(n-hexane/ethyl acetate¼6/1) to give 13 (981 mg, 93%) as a
NMR (CDCl3): d 1.51 (s, 9H) 1.81–1.88 (m, 2H), 2.10 (br
s, 1H), 2.71 (t, J¼7.2 Hz, 2H), 3.59 (m, 2H), 7.01–7.21
(m, 3H), 7.26 (br s, 1H), 7.71 (d, J¼6.7 Hz, 1H); 13C NMR
(CDCl3): d 26.5, 29.3, 32.3, 60.7, 80.1, 122.5, 124.1, 126.7,
129.5, 131.8, 136.3, 153.8. HRMS (FAB, NBA) calcd for
C14H21NO3: 251.1521 (M+); found: 251.1517. Anal. Calcd
for C14H21NO3: C, 66.91; H, 8.42; N, 5.57. Found: C,
67.04; H, 8.48; N, 5.52.
4.3.5. 1-tert-Butoxycarbonyl-1,2,3,4-tetrahydroquino-
line-2-o1 (17). A solution of oxalyl chloride (481 mg,
3.79 mmol) in CH2Cl2 (10 ml) was cooled at ꢁ78 ꢀC. A
solution of DMSO (462 mg, 5.92 mmol) in CH2Cl2 (5 ml)
was added dropwise at ꢁ78 ꢀC under a nitrogen atmosphere
and the reaction mixture was stirred at ꢁ78 ꢀC for 25 min. A
solution of 16 (359 mg, 1.44 mmol) in CH2Cl2 (6 ml) was
added dropwise. The mixture was stirred for an additional
35 min at ꢁ78 ꢀC, warmed to ꢁ40 ꢀC, and kept at ꢁ40 ꢀC
for 2 h. Then, Et3N (2.10 g, 0.79 mmol) was added slowly.
The reaction mixture was warmed to 0 ꢀC and stirred for
10 min at 0 ꢀC. After addition of saturated aqueous NH4Cl,
the mixture was extracted with ethyl acetate and washed with
brine. The organic phase was dried over MgSO4 and concen-
trated in vacuo. The residue was purified by silica gel column
chromatography (n-hexane/ethyl acetate¼3/1) to give 17
(224.5 mg, 63%) as yellow crystals: mp 55–63 ꢀC (ether/n-
1
yellow oil; IR: 3467, 3361, 2222, 1618 cmꢁ1; H NMR
(CDCl3): d 1.54–1.88 (m, 6H) 3.56–3.59 (m, 1H) 3.86–3.92
(m, 1H) 4.54 (d, J¼3.9 Hz, 2H), 4.91 (t, J¼3.5 Hz, 1H),
6.63–6.68 (m, 2H), 7.11 (dt, J¼7.8, 1.6 Hz, 1H), 7.28 (dd,
J¼7.7, 1.6 Hz, 1H). LRMS (FAB, NBA) m/z: 232 ([M+H]+).
4.3.2. 2-[3-(Tetrahydropyran-2-yloxy)propyl]phenyl-
amine (14). To a stirred solution of 13 (592 mg,
2.56 mmol) in methanol (13 ml) was added 5% Pd on carbon
(60 mg) under a nitrogen atmosphere. The reaction mixture
was stirred under a hydrogen atmosphere at room tempera-
ture. After 19 h, the reaction mixture was filtered through
a Celite pad and concentrated in vacuo. The residue was pu-
rified by silica gel column chromatography (n-hexane/ethyl
acetate¼6/1) to give 14 (562 mg, 93%) as a yellow oil; IR:
hexane); IR (KBr): 3448, 2976, 1678 cmꢁ1 1H NMR
;
1
3460, 3367, 1624 cmꢁ1; H NMR (CDCl3): d 1.55–1.94
(CDCl3): d 1.55 (s, 9H), 1.74–1.83 (m, 1H), 2.20–2.28 (m,
1H), 2.51–2.58 (m, 1H), 2.63–2.70 (m, 1H), 3.93 (br s,
1H), 5.79 (dt, J¼6.6, 3.1 Hz, 1H), 6.97–7.18 (m, 3H), 7.51
(d, J¼8.1 Hz, 1H); 13C NMR (CDCl3): d 24.6, 28.4, 31.0,
76.7, 81.3, 82.1, 123.5, 123.8, 125.6, 126.2, 27.2, 132.0,
136.3, 154.6. HRMS (FAB, NBA) calcd for C14H19NO3:
249.1365 (M+); found: 249.1367. Anal. Calcd for
C14H19NO3: C, 67.45; H, 7.68; N, 5.62. Found: C, 67.56;
H, 7.72; N, 5.63.
(m, 8H), 2.62 (dt, J¼7.6, 2.1 Hz, 2H), 3.42 (m, 2H), 3.78–
3.92 (m, 2H), 4.60 (m, 1H), 6.65–6.73 (m, 2H). LRMS
(FAB, NBA) m/z: 236 ([M+H]+).
4.3.3. 1-tert-Butoxycarbonylamino-2-[3-(tetrahydro-
pyran-2-yloxy)propyl]benzene (15). To a stirred solution
of 14 (18.5 g, 0.079 mol) in THF (100 ml) were added
Boc2O (25.7 g, 0.12 mol) in THF (50 ml) and Et3N (11.9 g,
0.12 mol) and the reaction mixture was stirred at room tem-
perature. After 24 h, the reaction mixture was diluted with
ethyl acetate and washed with 1 M KHSO4, water, and brine.
The organic phase was dried over MgSO4 and concentrated
in vacuo. The residue was purified by silica gel column chro-
matography (n-hexane/ethyl acetate¼6/1) to give 15 (25 g,
4.3.6. Ethyl 5-(2-tert-butoxycarbonylamino)phenyl-2-
pentenoate (18). To a stirred solution of 17 (192 mg,
0.774 mmol) in toluene (4 ml) was added (carbethoxy-
methylene)triphenylphosphorane (323 mg, 0.929 mmol) under
a nitrogen atmosphere and the reaction mixture was stirred at
100 ꢀC. After 12 h, the reaction mixture was diluted with
ethyl acetate and washed with water and brine. The
organic phase was dried over MgSO4 and concentrated in
vacuo. The residue was purified by silica gel column
1
93%) as a colorless oil; IR: 3336, 1730, 1539 cmꢁ1; H
NMR (CDCl3): d 1.40 (s, 9H), 1.55–1.81 (m, 6H), 1.85–1.92
(m, 2H), 2.65–2.78 (m, 2H), 3.34–3.39 (m, 1H), 3.49–3.52
(m, 1H), 3.69 (q, J¼5.4 Hz, 1H), 3.86–3.96 (m, 1H), 4.61

O. Hara et al. / Tetrahedron 63 (2007) 6170–6181
6177
chromatography (n-hexane/ethyl acetate¼8/1) to give 18
chromatography (n-hexane/ethyl acetate¼3/1) to give 21
(201 mg, 82%) as colorless crystals: mp 45–47 ꢀC (ether/
(192 mg, 100%) as a brown oil; IR: 3456, 3377, 3022,
1
1
n-hexane); IR (KBr): 3346, 2979, 1714, 1653 cmꢁ1; H
1734 cmꢁ1; H NMR (CDCl3): d 2.06 (s, 3H), 2.36–2.41
NMR (CDCl3): d 1.29 (t, J¼7.1 Hz, 3H), 1.52 (s, 9H),
2.48–2.54 (m, 2H), 2.70–2.74 (m, 2H), 4.20 (q, J¼7.1 Hz,
2H), 5.85–5.90 (m, 1H), 6.19 (br s, 1H), 6.98–7.24 (m, 4H),
7.69 (d, J¼7.8 Hz, 1H); 13C NMR (CDCl3): d 14.2, 28.3,
29.8, 32.0, 60.3, 80.5, 122.2, 123.1: 124.7, 127.2, 9.1,
131.5, 135.6, 147.5, 153.4, 166.4. HRMS (FAB, NBA) calcd
for C18H25NO4: 320.1862 ([M+H]+); found: 320.1853.
Anal. Calcd for C18H25NO4: C, 67.69; H, 7.89; N, 4.39.
Found: C, 67.82; H, 7.97; N, 4.42.
(m, 2H), 2.56–2.60 (m, 2H), 3.59 (br s, 2H), 4.52 (d,
J¼6.6 Hz, 2H), 5.60–5.67 (m, 1H), 5.82–5.89 (m, 1H),
6.67–6.75 (m, 2H), 7.02–7.06 (m, 2H); 13C NMR (CDCl3):
d 20.9, 30.5, 31.2, 64.9, 115.5, 118.6, 124.5, 125.4, 127.0,
129.3, 135.2, 144.0, 170.7. LRMS (FAB, NBA) m/z: 220
([M+H]+). Anal. Calcd for C13H17NO2: C, 71.21; H, 7.81;
N, 6.39. Found: C, 71.10; H, 7.99; N, 6.26.
4.3.10. 1-Toluenesulfonylamino-2-(5-acetoxy-3-pent-
enyl)benzene (22a). To a stirred solution of 21 (94.1 mg,
0.431 mmol) in pyridine (2 ml) at 0 ꢀC was added toluene-
sulfonyl chloride (98.7 mg, 0.518 mmol) and the reaction
mixture was stirred at room temperature. After 3 h, the reac-
tion mixture was treated with water (0.2 ml) for 30 min, di-
luted with ethyl acetate, and washed with 1 M hydrochloric
acid, water, and brine. The organic phase was dried over
MgSO4 and concentrated in vacuo. The residue was purified
by silica gel column chromatography (n-hexane/ethyl
acetate¼2/1) to give 22 (159 mg, 99%) as colorless crystals:
mp 75–80 ꢀC (ethyl acetate/n-hexane); IR (KBr): 3275,
4.3.7. 1-tert-Butoxycarbonylamino-2-(5-hydroxy-3-pent-
enyl)benzene (19). To a stirred solution of 18 (148 mg,
0.464 mmol) in toluene (2 ml) at ꢁ78 ꢀC was added 1.5 M
DIBAL in toluene (1.1 ml, 1.65 mmol) under a nitrogen at-
mosphere and the reaction mixture was stirred at ꢁ78 ꢀC.
After 2 h, the reaction mixture was quenched with Na2-
SO4$10H2O, filtered through a Celite pad, and concentrated
in vacuo. The residue was purified by silica gel column chro-
matography (n-hexane/ethyl acetate¼2/1) to give 19 (98 mg,
77%) as colorless crystals: mp 54–56 ꢀC (ethyl acetate/
1
1
n-hexane); IR (KBr): 3336, 2979, 1697 cmꢁ1; H NMR
2935, 1736 cmꢁ1; H NMR (CDCl3): d 2.07 (s, 3H), 2.13–
(CDCl3): d 1.52 (s, 9H), 1.64 (br s, 1H), 2.36 (q, J¼
7.2 Hz, 2H), 2.66 (t, J¼7.6 Hz, 2H), 4.06 (br s, 1H), 5.60–
5.76 (m, 2H), 6.30 (br s, 1H), 7.04–7.22 (m, 3H), 7.69 (d,
J¼8.0 Hz, 1H); 13C NMR (CDCl3): d 26.5, 27.7, 28.4,
28.9, 32.3, 60.4, 60.7, 60.9, 80.1, 122.4, 124.0, 126.7,
129.5, 131.7, 136.3, 153.8. HRMS (FAB, NBA) calcd for
C16H23NO3: 278.1756 ([M+H]+); found: 278.1760. Anal.
Calcd for C16H23NO3: C, 69.29; H, 8.36; N, 5.05. Found:
C, 69.19; H, 8.37; N, 4.96.
2.19 (m, 2H), 2.40 (s, 3H), 2.49–2.53 (m, 2H), 4.47 (d,
J¼6.4 Hz, 2H), 5.43–5.50 (m, 1H), 5.65–5.72 (m, 1H),
6.44 (br s, 1H), 7.10–7.24 (m, 6H), 7.62 (d, J¼8.0 Hz,
2H); 13C NMR (CDCl3): d 20.9, 21.4, 28.3, 30.0, 32.5,
41.4, 64.8, 124.9, 125.2, 126.5, 126.9, 127.2, 129.5, 129.8,
133.9, 134.5, 135.8, 136.7, 143.6, 170.9. HRMS (FAB,
NBA) calcd for C20H23NO4S: 374.1426 ([M+H]+); found:
374.1407. Anal. Calcd for C20H23NO4S: C, 64.32; H, 6.21;
N, 3.75. Found: C, 64.15; H, 6.38; N, 3.69.
4.3.8. 1-tert-Butoxycarbonylamino-2-(5-acetoxy-3-pent-
enyl)benzene (20). To a stirred solution of 19 (76.4 mg,
0.277 mmol) in pyridine (1.5 ml) was added acetic anhy-
dride (42.4 mg, 0.415 mmol) and the reaction mixture was
stirred at room temperature. After 12 h, the reaction mixture
was cooled to 0 ꢀC and treated with saturated aqueous
NaHCO3 (0.2 ml) for 30 min. The whole was extracted
with ethyl acetate. The organic phase was washed with
1 M hydrochloric acid and brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by silica
gel column chromatography (n-hexane/ethyl acetate¼6/1)
to give 20 (85 mg, 96%) as a colorless oil; IR: 3356, 2978,
4.3.11. 1-(N-2-Nitrobenzenesulfonyl)amino-2-(5-ace-
toxy-3-pentenyl)benzene (22b). To a stirred solution
of 21 (36.4 mg, 0.167 mmol) in pyridine (1 ml) at 0 ꢀC
was added 2-nitrobenzenesulfonyl chloride (55.5 mg,
0.250 mmol) and the reaction mixture was stirred for 18 h
at 23 ꢀC. The reaction mixture was diluted with ethyl acetate
and washed with 1 M hydrochloric acid, water, and brine.
The organic phase was dried over MgSO4 and concentrated
in vacuo. The residue was purified by silica gel column chro-
matography (n-hexane/ethyl acetate¼2/1) to give 22b
1H NMR (CDCl3): d 2.07 (s, 3H), 2.71–2.67 (m, 2H), 4.48
(dd, 2H, J¼6.3, 0.9 Hz), 5.46–5.53 (m, 1H), 5.69–5.76 (m,
1H), 7.23–7.10 (m, 4H), 7.61 (dt, 1H, J¼7.7, 1.2 Hz), 7.73
(dt, 1H, J¼7.7, 1.5 Hz), 7.79 (dd, 1H, J¼7.8, 1.3 Hz), 7.89
(dd, 1H, J¼8.0, 1.2 Hz); 13C NMR (CDCl3): d 13.1, 19.6,
21.3, 23.3, 27.3, 30.7, 39.1, 39.3, 39.5, 39.7, 39.9, 46.5, 47.5,
59.7, 60.9, 124.4, 124.8, 125.8, 127.4, 127.9, 131.1, 131.7,
134.2, 168.4. HRMS (FAB, NBA) calcd for C19H20N2O6S:
405.1114 ([M+H]+); found: 405.1089.
(70 mg, 99%) as a yellow oil; IR: 3307, 1735, 1542 cmꢁ1
;
1734 cmꢁ1 1H NMR (CDCl3): d 1.52 (s, 9H), 2.06 (s,
;
3H), 2.36 (q, J¼7.4 Hz, 2H), 2.66 (t, J¼7.8 Hz, 2H), 4.52
(d, J¼6.4 Hz, 2H), 5.58–5.65 (m, 1H), 5.79–5.86 (m, 1H),
6.27 (br s, 1H), 7.03–7.22 (m, 3H), 7.71 (d, J¼7.6 Hz,
1H); 13C NMR (CDCl3): d 20.9, 28.3, 30.6, 32.2, 64.9, 0.4,
122.7, 124.3, 125.0, 126.9, 129.2, 131.8, 134.7, 135.6,
153.4, 170.8. HRMS (FAB, NBA) calcd for C18H25NO4:
320.1862 ([M+H]+); found: 320.1872.
4.3.9. 2-(5-Acetoxy-3-pentenyl)aniline (21). To a stirred
solution of 20 (387.1 mg, 1.22 mmol) at 0 ꢀC was added tri-
fluoroacetic acid (2 ml) and the reaction mixture was stirred
at 0 ꢀC. After 2 h, the reaction mixture was poured into sat-
urated aqueous NaHCO3 and extracted with ethyl acetate.
The organic phase was washed with saturated aqueous
NaHCO3, water, and brine, dried over MgSO4, and concen-
trated in vacuo. The residue was purified by silica gel column
4.3.12. 1-(N-4-Nitrobenzenesulfonyl)amino-2-(5-ace-
toxy-3-pentenyl)benzene (22c). Compound 22c was pre-
pared from 21 using 4-nitrobenzenesulfonyl chloride as
described in Section 4.3.11.
The crude product was purified by silica gel column chroma-
tography (n-hexane/EtOAc¼2/1). Compound 22c: a yellow
oil; IR: 3273, 3105, 2937, 1736, 1531 cmꢁ1 1H NMR
;

6178
O. Hara et al. / Tetrahedron 63 (2007) 6170–6181
(CDCl3): d 2.08 (s, 3H), 2.24–2.19 (m, 2H), 2.60–2.56 (m,
2H), 4.48 (d, 2H, J¼6.1 Hz), 5.45–5.38 (m, 1H), 5.72–
5.65 (m, 1H), 6.75 (br s, 1H), 7.00–7.24 (m, 4H), 7.93 (d,
2H, J¼8.7 Hz), 8.31 (d, 2H, J¼8.7 Hz); 13C NMR CDCl3):
d 13.1, 19.6, 21.3, 23.3, 27.3, 30.7, 46.5, 47.5, 59.7, 60.9,
124.4, 124.9, 125.8, 127.5, 128.0, 131.1, 131.7, 134.2, 168.4.
HRMS (FAB, NBA) calcd for C19H20N2O6S: 405.1114
([M+H]+); found: 405.1121.
(2.89 g, 10.9 mmol) as described in Section 4.3.5. Com-
pound 27: yellow oil; IR: 3387, 2979, 1637 cmꢁ1 1H
;
NMR (CDCl3): d 1.40 (s, 9H), 1.62–2.83 (m, 6H), 7.03–
7.25 (m, 4H), 9.77 (s, 1H); 13C NMR (CDCl3): d 21.9, 22.0,
27.8, 27.9, 28.2, 28.3, 30.1, 30.5, 43.0, 43.4, 82.6, 126.9,
127.1, 128.0, 128.6, 129.3, 129.4, 138.2, 151.7. HRMS
(EI) calcd for C15H21NO3: 263.1521 (M+); found: 263.1516.
4.3.18. Ethyl 6-(2-tert-butoxycarbonylamino)phenyl-2-
hexenoate (28). Compound 28 (2.11 g, 89%) was prepared
from 27 (1.86 g, 7.1 mmol) as described in Section 4.3.6.
Compound 28: pale yellow oil; IR: 3354, 2979, 2932,
4.3.13. 2-[4-(Tetrahydropyran-2-yloxy)but-1-ynyl]phe-
nylamine (23). Compound 23 (5.34 g, 68%) was prepared
from 12 (7.0 g, 32 mmol) using O-tetrahydropyranyl-
butyn-4-ol as described in Section 4.3.1. Compound 23:
1
1722 cmꢁ1; H NMR (CDCl3): d 1.23–1.32 (m, 3H), 1.39
1
yellow oil; IR: 3456, 3368, 2944, 1616 cmꢁ1; H NMR
(s, 9H), 1.71–1.83 (m, 2H), 2.18–2.32 (m, 2H), 2.49–2.64
(m, 2H), 4.16–4.24 (m, 2H), 5.77–5.91 (m, 1H), 6.22 (s,
1H), 6.88–7.37 (m, 4H), 7.72 (d, J¼8.0 Hz, 1H); 13C
NMR (CDCl3): d 14.2, 27.8, 27.8, 28.3, 29.0, 30.4, 30.5,
30.8, 31.6, 31.9, 60.1, 80.4, 82.5, 121.6, 121.9, 122.7,
124.3, 126.6, 126.8, 126.9, 127.9, 128.4, 128.5, 129.1, 129.3,
131.9, 135.6, 137.9, 138.6, 148.2, 148.4, 149.3, 151.6, 153.3,
166.5. HRMS (FAB, NBA) calcd for C19H27NO4: 333.1940
(M+); found: 333.1941.
(CDCl3): d 1.48–1.92 (m, 7H), 2.77 (t, J¼13.6 Hz, 2H),
3.44–3.58 (m, 1H), 3.63–3.71 (m, 1H), 3.88–3.98 (m,
2H), 4.16–4.31 (br, 2H), 4.69 (t, J¼6.8 Hz, 1H), 6.66 (m,
2H), 7.08 (dt, J¼1.6, 7.4 Hz, 1H), 7.23 (dd, J¼1.6, 9.2 Hz,
1H); 13C NMR (CDCl3): d 19.3, 21.0, 25.2, 30.4, 62.1, 65.7,
65.9, 78.0, 92.9, 98.6, 108.2, 113.9, 117.4, 128.8, 131.7,
147.8. HRMS (FAB, NBA) calcd for C15H19NO2: 245.1416
(M+); found: 245.1410.
4.3.14. 2-[4-(Tetrahydropyran-2-yloxy)butyl]phenyl-
amine (24). Compound 24 (5.09 g, 94%) was prepared
from 23 (5.34 g, 21.8 mmol) as described in Section 4.3.2.
Compound 24: yellow oil; IR: 3447, 3369, 2939, 2864,
1624 cmꢁ1; 1H NMR (CDCl3): d 1.46–1.88 (m, 10H), 2.52
(t, J¼8.4 Hz, 2H), 3.33–3.55 (m, 2H), 3.55–3.75 (m, 2H),
3.75–3.94 (m, 2H), 4.57 (t, J¼4.0 Hz, 1H), 6.66 (d,
J¼8.0 Hz, 1H), 6.71 (t, J¼8.4 Hz, 1H), 7.02 (t, J¼8.8 Hz,
2H); 13C NMR (CDCl3): d 19.7, 25.4, 25.5, 29.4, 30.7, 30.9,
62.4, 67.2, 98.9, 115.5, 118.6, 126.5, 126.9, 129.5, 144.1.
HRMS (FAB, NBA) calcd for C15H23NO2: 249.1729 (M+);
found: 249.1724.
4.3.19. 1-tert-Butoxycarbonylamino-2-(6-hydroxy-4-hex-
enyl)benzene (29). Compound 29 (1.84 g, quant.) was pre-
pared from 28 (2.11 g, 6.33 mmol) as described in Section
4.3.7. Compound 29: pale yellow oil; IR: 3385, 2987,
1
2931, 2086, 1653 cmꢁ1; H NMR (CDCl3): d 1.52 (s, 9H),
1.71 (quin, J¼7.6 Hz, 2H), 2.07–2.16 (m, 2H), 2.58 (t,
J¼7.8 Hz, 2H), 4.07–4.18 (m, 2H), 5.65–5.77 (m, 2H),
6.63 (s, 1H), 7.04 (dt, J¼1.2, 7.2 Hz, 1H), 7.14 (dd, J¼1.6,
7.6 Hz, 1H), 7.19 (dt, J¼2.0, 7.6 Hz, 1H), 7.71 (d, J¼
4.0 Hz, 1H); 13C NMR (CDCl3): d 26.7, 28.3, 29.0, 29.3,
30.2, 30.6, 31.4, 58.5, 63.6, 80.6, 122.5, 124.2, 126.7, 129.3,
129.4, 130.2, 132.1, 132.3, 135.6, 153.5. HRMS (FAB,
NBA) calcd for C17H25NO3: 292.1913 ([M+H]+); found:
292.1904.
4.3.15. 1-tert-Butoxycarbonylamino-2-[4-(tetrahydro-
pyran-2-yloxy)butyl]benzene (25). Compound 25 (6.42 g,
90%) was prepared from 24 (5.09 g, 20.4 mmol) as de-
scribed in Section 4.3.3. Compound 25: pale yellow oil;
IR: 2940, 2867, 1790, 1730, 1455 cmꢁ1; 1H NMR (CDCl3):
d 1.39 (s, 9H), 1.47–1.85 (m, 12H), 2.57 (m, 2H), 3.32–3.57
(m, 2H), 3.68–3.97 (m, 2H), 4.57 (q, J¼5.0 Hz, 1H), 6.98–
7.35 (m, 4H); 13C NMR (CDCl3): d 18.3, 19.5, 19.6, 25.3,
26.3, 26.4, 27.3, 27.8, 28.3, 29.3, 29.7, 30.6, 30.7, 30.9, 62.2,
62.4, 67.2, 67.3, 67.6, 80.3, 98.9, 124.0, 126.3, 126.6, 127.8,
129.2, 129.3, 135.6, 137.8, 139.2, 151.6, 153.3. HRMS (EI)
calcd for C20H31NO4: 349.2253 (M+); found: 349.2262.
4.3.20. 1-tert-Butoxycarbonylamino-2-(6-acetoxy-4-hex-
enyl)benzene (30). Compound 30 (1.52 g, 87%) was pre-
pared from 29 (1.52 g, 5.23 mmol) as described in Section
4.3.8. Compound 30: pale yellow oil; IR: 3387, 2082,
1
1645 cmꢁ1; H NMR (CDCl3): d 1.52 (s, 9H), 1.65–1.75
(m, 2H), 2.05–2.23 (m, 5H), 2.56 (t, J¼8.0 Hz, 2H), 4.53
(d, J¼7.2 Hz, 2H), 5.56–5.67 (m, 1H), 5.75–5.84 (m, 1H)
6.27 (s, 1H) 7.04 (t, J¼7.2 Hz, 1H), 7.13 (dd, J¼1.6, 8.0 Hz,
1H), 7.19 (dt, J¼1.6, 7.2 Hz, 1H), 7.73 (d, J¼7.2 Hz, 1H);
13C NMR (CDCl3): d 21.0, 27.1, 28.3, 28.7, 29.2, 30.5,
31.7, 60.3, 65.1, 80.4, 122.4, 124.1, 124.3, 126.8, 129.3,
134.4, 135.6, 153.3, 170.8. HRMS (FAB, NBA) calcd for
C19H28NO4: 334.2018 ([M+H]+); found: 334.2012.
4.3.16. 1-tert-Butoxycarbonylamino-2-(4-hydroxybutyl)-
benzene (26). Compound 26 (2.89 g, 59%) was prepared
from 25 (6.42 g, 18.4 mmol) as described in Section 4.3.4.
Compound 26: pale yellow oil; IR: 3427, 1695, 1523 cmꢁ1
;
4.3.21. 2-(6-Acetoxy-4-hexenyl)aniline (31). Compound
31 (1.52 g, 87%) was prepared from 30 (1.52 g,
5.23 mmol) as described in Section 4.3.9. Compound 31:
1H NMR (CDCl3): d 1.52 (s, 9H), 1.57–1.73 (m, 4H), 2.61 (t,
J¼7.4 Hz, 2H), 3.71 (q, J¼7.6 Hz, 2H), 6.99–7.26 (m, 4H);
13C NMR (CDCl3): d 25.7, 26.0, 27.8, 28.3, 30.6, 30.8, 31.6,
32.5, 62.5, 80.3, 82.5, 122.3, 124.1, 126.4, 126.7, 127.9,
128.4, 129.2, 129.3, 135.7, 137.8, 139.2, 151.8, 153.5.
HRMS (FAB, NBA) calcd for C15H23NO3: 265.1678 (M+);
found: 265.1674.
yellow oil; IR: 3387, 2933, 2859, 2068, 1731, 1629 cmꢁ1
;
1H NMR (CDCl3): d 1.73 (m, 2H), 2.05–2.24 (m, 5H), 2.49
(t, J¼8.0 Hz, 2H), 4.52 (d, J¼6.4 Hz, 2H), 5.55–5.66 (m,
1H), 5.75–5.88 (m, 1H), 6.67 (dd, J¼0.8, 8.0 Hz, 1H), 6.73
(t, J¼6.8 Hz, 1H), 6.99–7.06 (m, 2H); 13C NMR (CDCl3): d
20.8, 27.6, 30.3, 31.8, 53.3, 65.0, 115.4, 118.5, 124.3, 126.0,
126.8, 129.3, 135.6, 143.9, 170.6. HRMS (FAB, NBA) calcd
for C14H19NO2: 233.1416 (M+); found: 233.1418.
4.3.17. 4-(2-tert-Butoxycarbonylamino)phenyl-butanal
(27). Compound 27 (1.86 g, 65%) was prepared from 23

O. Hara et al. / Tetrahedron 63 (2007) 6170–6181
6179
4.3.22. 1-Toluenesulfonylamino-2-(6-acetoxy-4-hexenyl)-
benzene (32). Compound 31 (117 mg, 47%) was prepared
from 28 (115 mg, 0.66 mmol) as described in Section
4.3.10. Compound 32: pale yellow oil; IR: 3447, 2080, 1731,
1637 cmꢁ1; 1H NMR (CDCl3): d 1.47 (quin, J¼8.0 Hz, 2H),
1.99 (q, J¼7.2 Hz, 2H), 2.08 (s, 3H), 2.34 (t, J¼7.6 Hz, 2H),
2.39 (s, 3H), 4.53 (dd, J¼1.2, 6.4 Hz, 2H), 5.50–5.61 (m,
1H), 5.64–6.76 (m, 1H), 6.35 (s, 1H), 7.07–7.31 (m, 6H),
7.61 (d, J¼8.0 Hz, 1H); 13C NMR (CDCl3): d 21.0, 21.5,
28.9, 29.9, 31.6, 65.1, 124.6, 124.6, 124.7, 126.3, 126.9,
127.2, 128.0, 129.4, 129.5, 129.7, 129.7, 133.9, 135.3,
135.5, 136.7, 143.7, 170.9. HRMS (FAB, NBA) calcd for
C21H26NO4S: 388.1583 ([M+H]+); found: 388.1590.
atmosphere. The sulfonamide 22a (29.7 mg, 0.0806 mmol)
in THF (2 ml) was added to the solution at ꢁ15 ꢀC. The clear
solution was degassed by three freeze–thaw cycles and
stirred for 30 min at ꢁ15 ꢀC. The reaction mixture was
heated to reflux for 3 h, and allowed to cool to room temper-
ature, quenched with saturated aqueous NH4Cl, extracted
with ethyl acetate, and washed with water and brine. The
organic phase was dried over MgSO4 and concentrated in
vacuo. The residue was purified by silica gel column chro-
matography (n-hexane/ethyl acetate¼10/1) to give 36a
(18.9 mg, 76%) as a yellow oil; IR: 3066, 3021, 2927,
1652 cmꢁ1; 1H NMR (CDCl3): d 1.55–1.63 (m, 1H), 1.77–
1.85 (m, 1H), 1.97–2.04 (m, 1H), 2.38 (s, 3H), 2.43–2.50 (m,
1H), 4.89–4.92 (m, 1H), 5.11 (dd, J¼10.5, 1.2 Hz, 1H), 5.28
(dd, J¼17.1, 1.2 Hz, 1H), 5.74–5.82 (m, 1H), 6.96–7.23 (m,
5H), 7.44 (d, J¼8.3 Hz, 2H), 7.78 (d, J¼8.3 Hz, 1H); 13C
NMR (CDCl3): d 21.5, 24.3, 27.4, 57.2, 77.4, 116.0, 125.2,
126.3, 126.7, 127.1, 128.3, 129.0, 129.5, 132.1, 135.5,
136.5, 137.0, 143.4. HRMS (FAB, NBA) calcd for
C18H19NO2S: 313.1137 (M+); found: 313.1132.
4.3.23. 1-Toluenesulfonylamino-2-(4-chloro-2-butenyl)-
benzene (34). To a stirred solution of N-(2-iodophenyl) tolu-
enesulfonamide (33, 1.12 g, 3 mmol) in THF (15 ml) at
ꢁ78 ꢀC under an argon atmosphere was added dropwise
a 1.6 M solution of n-butyl lithium in hexane (4 ml,
6.4 mmol) and the reaction mixture was stirred at same tem-
perature for 1 h. Then 1,4-dichloro-2-butene (0.75 g,
6 mmol) was added at ꢁ78 ꢀC. The reaction mixture was al-
lowed to warm to room temperature and stirred for 24 h and
quenched with saturated aqueous NaHCO3. The whole was
extracted with ethyl acetate. The organic layer was washed
with 10% aqueous citric acid, dried over Na2SO4, and con-
centrated in vacuo. The residue was chromatographed on sil-
ica gel (chloroform) to give 34 (473 mg, 47%) as a yellow
4.4.2. N-Tosyl-2-allyl-1,2,3,4-tetrahydroquinoline (36a)
using (S)-9-PBN. To a stirred solution of Pd(dba)2 (0.9 mg,
0.00149 mmol) and lithium acetate (4.9 mg, 0.0744 mmol)
in THF (1 ml) was added 0.1 M (S)-9-PBN (0.0298 ml,
0.00298 mmol) in heptane at ꢁ15 ꢀC under an argon atmo-
sphere. The mixture was degassed by three freeze–thaw
cycles and stirred for 30 min at ꢁ15 ꢀC. The sulfonamide
22a (27.7 mg, 0.0744 mmol) in THF (2 ml) and N,O-bis(tri-
methylsilyl)acetamide (0.0552 ml, 0.223 mmol) were added
to the solution at ꢁ15 ꢀC. The clear solution was stirred for
30 min at ꢁ15 ꢀC, warmed to room temperature, and stirred
for 20 h. The reaction mixture was quenched with saturated
aqueous NH4Cl, extracted with ethyl acetate, and washed
with water and brine. The organic phase was dried over
MgSO4 and concentrated in vacuo. The residue was purified
by silica gel column chromatography (n-hexane/ethyl
acetate¼10/1–2/1) to give 36a (15.9 mg, 68%, 72% ee) as
a yellow oil. The HPLC analysis of 36a was carried out using
the Daicel Chiralcel OD-H column (n-hexane/i-PrOH¼
99/1, flow rate: 0.5 ml/min, UV 254 nm). (S)-Isomer:
27.8 min and (R)-isomer: 30.3 min (major).
1
oil; IR: 3065, 2923 cmꢁ1; H NMR (CDCl3): d 2.43 (s,
3H), 3.91 (d, J¼6.0 Hz, 2H), 4.18 (d, J¼6.4 Hz, 2H),
5.61–5.78 (m, 2H), 7.00–7.06 (m, 2H), 7.22–7.34 (m, 4H),
7.48 (d, J¼8.4 Hz, 2H); 13C NMR (CDCl3): d 21.5, 43.8,
52.1, 127.7, 127.9, 128.8, 129.0, 129.4, 130.0, 135.4, 139.1,
143.5. HRMS (FAB, NBA) calcd for C17H24ClNO2S:
336.0825 ([M+H]+); found: 336.0816.
4.3.24. 1-Toluenesulfonylamino-2-(4-acetoxy-2-butenyl)-
benzene (35). To a stirred solution of 34 (473 mg,
1.41 mmol) in DMSO (7 ml) at room temperature was added
potassium acetate (166 mg, 1.69 mmol) and the reaction
mixture was stirred for 12 h. The reaction mixture was di-
luted with water and extracted with ethyl acetate. The or-
ganic layer was dried over Na2SO4 and concentrated in
vacuo. The residue was chromatographed on silica gel (n-
hexane/ethyl acetate¼4/1) to give 35 (424 mg, 83%) as yꢁe1l-
4.4.3. N-(2-Nitrobenzenesulfonyl)-2-allyl-1,2,3,4-tetra-
hydroquinoline (36b). The reaction of 22b was carried
out as described in Section 4.4.2. Yield: 51% and 56% ee.
Compound 36b: yellow crystals: mp 92–94 ꢀC; IR (KBr):
low solids: mp 94–95 ꢀC; IR (KBr): 3461, 3046, 2917 cm
;
1H NMR (CDCl3): d 2.00 (s, 3H), 2.43 (s, 3H), 4.18 (dd,
J¼0.8, 6.0 Hz, 2H), 4.41 (dd, J¼1.2, 6.0 Hz, 2H), 5.56–
5.74 (m, 2H), 7.00–7.05 (m, 2H), 7.22–7.32 (m, 2H), 7.48
(d, J¼8.4 Hz, 2H); 13C NMR (CDCl3): d 20.8, 21.6, 52.3,
63.8, 127.7, 127.9, 128.2, 128.3, 128.9, 129.1, 129.4, 129.5,
135.5, 139.1, 143.5, 170.5. HRMS (FAB, NBA) calcd for
C19H21NO4S: 360.1270 ([M+H]+); found: 360.1268. Anal.
Calcd for C19H21NO4S: C, 63.49; H, 5.89; N, 3.90. Found:
C, 63.35; H, 5.80; N, 3.90.
1
3088, 2940, 1548, 1375 cmꢁ1; H NMR (CDCl3): d 1.66–
1.74 (m, 1H), 2.23–2.15 (m, 1H), 2.33–2.26 (m, 1H), 2.52–
2.58 (m, 1H), 5.05–5.14 (m, 2H), 5.27–5.32 (m, 1H),
5.74–5.82 (m, 1H), 7.02–7.24 (m, 3H), 7.45–7.71 (m, 5H);
13C NMR (CDCl3): d 24.7, 28.6, 57.7, 78.7, 116.3, 123.8,
125.8, 125.9, 126.9, 128.5, 31.0, 131.1, 132.2, 133.1, 133.6,
134.8, 136.8. HRMS (FAB, NBA) calcd for C17Hl6N2O4S:
344.0831 (M+); found: 344.0835. Anal. Calcd for
C17Hl6N2O4S: C, 59.29; H, 4.68; N, 8.13. Found: C, 59.07;
H, 4.67; N, 8.27. The HPLC analysis of 36b was carried
out using the Daicel Chiralpak AD column (n-hexane/
i-PrOH¼2/1 (0.1% Et2NH), flow rate: 0.5 ml/min, UV
254). (S)-Isomer: 11.2 min and (R)-isomer: 12.5 min.
4.4. Synthesis of chiral tetrahydroquinolines and
relatives
4.4.1. (rac)-N-Tosyl-2-allyl-1,2,3,4-tetrahydroquinoline
((rac)-36a). A mixture of Pd(dba)2 (2.3 mg, 0.00403 mmol)
and triphenylphosphine (2.1 mg, 0.00806 mmol) in THF
(1 ml) was stirred for 30 min at ꢁ15 ꢀC under an argon
4.4.4. N-(4-Nitrobenzenesulfonyl)-2-allyl-1,2,3,4-tetrahy-
droquinoline (36c). The reaction of 22c was carried out as

6180
O. Hara et al. / Tetrahedron 63 (2007) 6170–6181
described in Section 4.4.2. Yield: 86% and 65% ee. 36c: yel-
low crystals: mp 65–72 ꢀC; IR (KBr): 3098, 2954, 1606,
1528 cmꢁ1; 1H NMR (CDCl3): d 1.68–1.57 (m, 1H), 1.97–
1.81 (m, 2H), 2.53–2.46 (m, 1H), 4.93–4.91 (m, 1H), 5.16
(d, J¼13.7 Hz, 1H), 5.30 (d, J¼16.1 Hz, 1H), 5.84–5.76 (m,
1H), 6.99–7.28 (m, 3H), 7.77 (d, J¼8.2 Hz, 1H), 7.72 (d, J¼
9.0 Hz, 2H), 8.23 (d, J¼9.0 Hz, 2H); 13C NMR (CDCl3):
d 24.5, 28.0, 30.0, 116.5, 124.1, 126.1, 126.3, 127.1, 28.3,
128.6, 132.4, 134.7, 136.4, 145.0, 150.0. HRMS (FDA,
NBA) calcd for C17H16N2O4S: 344.0831 (M+); found:
344.0825. Anal. Calcd for C17Hl6N2O4S: C, 59.29; H, 4.68;
N, 8.13. Found: C, 59.31; H, 4.79; N, 7.90. The HPLC anal-
ysis of 36c was carried out using the Daicel Chiralcel OD-H
(n-hexane/i-PrOH¼9/1, flow rate: 0.5 ml/min, UV 254 nm).
(S)-Isomer: 26.0 min and (R)-isomer: 38.8 min.
4.5. Determination of the absolute configuration for 36a
4.5.1. 2-[1-(Toluene-4-sulfonyl)-1,2,3,4-tetrahydroquino-
lin-2-yl]ethanol. To a stirred solution of (ꢁ)-36a ([a]D26
ꢁ7.88 (c 1.21, CHCl3), 24% ee, 104 mg, 0.33 mmol) in
THF (2 ml) was added borane dimethylsulfide complex
(0.032 ml, 0.33 mmol) and the reaction mixture was stirred
at 23 ꢀC for 2 h. The reaction mixture was allowed to cool
to 0 ꢀC, diluted with water, and treated with 3 M NaOH
(1 ml) and 30% hydrogen peroxide (1 ml). After stirring
the mixture for 2 h, the mixture was extracted with ethyl ace-
tate and the extract was washed with water and brine. The
organic layer was dried over Na2SO4, filtered, and concen-
trated in vacuo. The residue was chromatographed on silica
gel (n-hexane/ethyl acetate¼1/2) to give the alcohol (53 mg,
48%) as a colorless oil: [a]2D0 ꢁ112 (c 1.50, CHCl3); IR:
1
4.4.5. N-Tosyl-2-allyl-1,2,3,4-tetrahydroquinoline (36a)
using (R)-9-NapBN. To a stirred solution of [(allyl)PdCl]2
(1.3 mg, 0.0035 mmol) and lithium acetate (9.2 mg,
0.14 mmol) in THF (0.5 ml) at 23 ꢀC under an argon atmo-
sphere was added 0.2 M (R)-9-NapBN (0.070 ml,
0.014 mmol) in toluene. N,O-Bis(trimethylsilyl)acetamide
(85 mg, 0.42 mmol) and a 1 M solution of the sulfonamide
22a in toluene (140 ml, 0.14 mmol) were added to the solu-
tion at 23 ꢀC. The reaction mixture was stirred for 18 h. The
reaction mixture was quenched with saturated aqueous
NH4Cl, extracted with ethyl acetate, and washed with water
and brine. The organic phase was dried over MgSO4 and
concentrated in vacuo. The residue was purified by silica
gel column chromatography (n-hexane/ethyl acetate¼7/1)
give 36a (27 mg, 61%, 94% ee) as a yellow oil: [a]D20
ꢁ91.2 (c 0.62, CHCl3).
3532, 3406, 2928, 1598, 1487 cmꢁ1; H NMR (CDCl3):
d 1.31–1.38 (m, 1H), 1.47–1.53 (m, 1H), 1.61–1.70 (m,
1H), 1.82–1.89 (m, 1H), 2.38 (s, 3H), 2.41–2.43 (m, 1H),
272–2.98 (m, 1H), 3.06–3.68 (m, 1H), 3.92–3.99 (m, 1H),
4.45–4.51 (m, 1H), 6.99 (d, J¼8.3 Hz, 1H), 7.14 (dt, J¼
1.2, 8.3 Hz, 1H), 7.18 (d, J¼8.3 Hz, 2H), 7.22–7.73 (m, 2H),
7.39 (d, J¼6.3 Hz, 2H), 7.77 (dd, J¼1.0, 8.3 Hz, 1H).
4.5.2. [1-(Toluene-4-sulfonyl)-1,2,3,4-tetrahydroquino-
lin-2-yl]acetic acid methyl ester. To a stirred solution of
the above alcohol (22 mg, 0.067 mmol) in acetone (1 ml)
was added Jones’ reagent (4 equiv) at ꢁ15 ꢀC and the reac-
tion mixture was stirred at ꢁ15 ꢀC for 30 min. The reaction
mixture was quenched with 2-propanol and extracted with
CHCl3. The extract was washed with water and brine. The
organic layer was dried over Na2SO4, filtered, and concen-
trated in vacuo to give the carboxylic acid, which was used
for the next esterification without any purification. The resi-
due was dissolved in DMF (0.5 ml) and treated with KHCO3
(13 mg, 0.13 mmol) and iodomethane (0.006 ml) and the
reaction mixture was stirred at 23 ꢀC for 18 h. The reaction
mixture was diluted with ethyl acetate and washed with
water and brine. The organic layer was dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was
chromatographed on silica gel (n-hexane/ethyl acetate¼
4/1) to give the methyl ester (15 mg, 62% in two steps) as
4.4.6. 1-(Toluene-4-sulfonyl)-2-vinyl-2,3,4,5-tetrahydro-
1H-benzo[b]azepine (37). The reaction of 32 was carried
out as described in Section 4.4.5. Yield: 29% and 55% ee.
1
Compound 37: pale yellow oil; IR: 3411, 2940 cmꢁ1; H
NMR (CDCl3): d 1.43–1.75 (m, 3H), 1.89–2.03 (m, 1H),
2.40–2.47 (m, 5H), 5.02 (d, J¼10.4 Hz, 2H), 5.17 (d,
J¼18 Hz, 2H), 5.49–5.64 (m, 1H), 7.06–7.30 (m, 6H),
7.62 (d, J¼8.0 Hz, 2H); 13C NMR (CDCl3): d 20.8, 21.4,
32.5, 58.9, 116.3, 125.3, 126.6, 127.5, 128.3, 128.9, 129.3,
129.7, 130.4, 131.3, 136.6, 138.8, 141.7, 143.0, 143.2.
HRMS (FAB, NBA) calcd for C19H21NO2S: 327.1293
(M+); found: 327.1294. The HPLC analysis of 37 was car-
ried out using the Daicel Chiralcel OD-H column (n-hex-
ane/i-PrOH¼99/1, flow rate: 0.5 ml/min, UV 254 nm). tR:
24.825 and 27.375 min (major).
1
a colorless oil: [a]D13 ꢁ13.2 (c 0.755, CHCl3); H NMR
(CDCl3): d 1.37–1.42 (m, 1H), 1.64–1.75 (m, 1H), 1.95–
2.25 (m, 1H), 2.30–2.35 (m, 1H), 2.37 (s, 3H), 2.45–2.52
(m, 1H), 2.83–2.87 (m, 1H), 3.67 (s, 3H), 4.60–4.65 (m,
1H), 6.96 (d, J¼7.6 Hz, 1H), 7.12–7.15 (m, 1H), 7.16 (d, J¼
8.3 Hz, 2H), 7.22–7.24 (m, 1H), 7.36 (d, J¼8.3 Hz, 2H),
7.70 (d, J¼8.3 Hz, 1H).
4.4.7. 1-(Toluene-4-sulfonyl)-2-vinyl-2,3-dihydro-1H-in-
dole (38). The reaction of 35 was carried out by using (S)-
NapBN as described in Section 4.4.5. Yield: 1.2% and
61.5% ee. Compound 38: yellow oil; IR: 3065, 2919, 1596,
1492, 1349, 1165 cmꢁ1; 1H NMR (CDCl3): d 2.37 (s, 3H),
3.54–3.61 (m, 1H), 3.74 (q, J¼9.6 Hz, 1H), 4.17 (t, 1H) 5.01–
5.11 (m, 1H), 5.47–5.59 (m, 1H), 7.00 (d, J¼4.8 Hz, 2H),
7.12–7.25 (m, 3H), 7.62–7.70 (m, 3H); 13C NMR (CDCl3):
d 21.5, 44.8, 55.6, 115.1, 117.1, 123.9, 125.1, 127.3, 128.3,
129.6, 133.8, 133.9, 137.3, 141.7, 144.1. HRMS (EI) calcd
for C17H17NO2S: 299.0980 (M+); found: 299.0982. The
HPLC analysis of 38 was carried out using the Daicel Chiral-
cel OD-H column (n-hexane/i-PrOH¼99/1, flow rate:
0.5 ml/min, UV 254 nm). tR: 25.508 (major) and 28.117 min.
4.5.3. (1,2,3,4-Tetrahydroquinolin-2-yl)acetic acid methyl
ester (41). To a stirred solution of the above methyl ester
(15.4 mg, 0.043 mmol) in methanol (1 ml) at 23 ꢀC was
added magnesium turning (42 mg, 1.7 mmol) and the reaction
mixture was stirred at 23 ꢀC for 5 h. The reaction mixture was
diluted with ethyl acetate and extracted with chloroform. The
extract was washed with water and brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was chroma-
tographed on silica gel (n-hexane/ethyl acetate¼2/1) to give
41 (6.5 mg, 74%) as a colorless oil: [a]2D5 ꢁ22.6 (c 0.415,
1
CHCl3); IR: 3394, 2924, 2849, 1732, 1607, 1488 cmꢁ1; H
NMR (CDCl3): d 1.67–1.76 (m, 1H), 1.92–1.99 (m, 1H),
2.52 (d, J¼6.8 Hz, 2H), 2.69–2.75 (m, 1H), 2.80–2.88 (m,

O. Hara et al. / Tetrahedron 63 (2007) 6170–6181
6181
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1H), 3.72 (s, 3H), 4.50 (br s, 1H), 6.50 (d, J¼8.1 Hz, 1H), 6.62
(t, J¼7.3 Hz, 1H), 6.94–6.99 (m, 2H). The absolute configu-
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Accordingly, (ꢁ)-36a was confirmed to bear (R)-configura-
tion.
Acknowledgements
This work was financially supported in part by a Grant-in-
Aid for Scientific Research (B) from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan. We are
grateful to Dr. Ryu Nagata at the Dainippon Sumitomo
Pharma Co. for the gift of methyl (S)-1,2,3,4-tetrahydroqui-
noline-2-acetate and Mr. H. Uchida at the Meito Sangyo Co.
for the generous gift of lipase My.
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