Asymmetric synthesis of 2-substituted hexahydroquinolin-4-ones using a Pd-catalyzed asymmetric allylic amination and intramolecular Mannich reaction: Catalytic asymmetric synthesis of 2-epi-cis-195A

Article abstract of DOI:10.1055/s-0030-1260102

A novel method of the enantioselective synthesis of 2-substituted hexahydroquinolin-4-ones is described. The method relies on a Pd-catalyzed asymmetric allylic amination using a chiral diaminophosphine oxide (DIAPHOX) preligand and diastereoselective intr

Full text of DOI:10.1055/s-0030-1260102

2540
FEATURE ARTICLE
Asymmetric Synthesis of 2-Substituted Hexahydroquinolin-4-ones Using a
Pd-Catalyzed Asymmetric Allylic Amination and Intramolecular Mannich
Reaction: Catalytic Asymmetric Synthesis of 2-epi-cis-195A
A
symmetric Synth
a
esis of 2-Su
z
bstituted H
u
exahydroqui
m
nolin-4-ones i Kakugawa, Tetsuhiro Nemoto, Yuta Kohno, Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33, Yayoi-cho, Inage-ku, 263-8522, Japan
Fax +81(43)2902987; E-mail: hamada@p.chiba-u.ac.jp
Received 12 May 2011; revised 5 June 2011
been achieved using chiral auxiliaries11 or a catalytic
Abstract: A novel method of the enantioselective synthesis of 2-
substituted hexahydroquinolin-4-ones is described. The method re-
lies on a Pd-catalyzed asymmetric allylic amination using a chiral
diaminophosphine oxide (DIAPHOX) preligand and diastereose-
asymmetric synthesis.12 Natural or unnatural epimers of
cis-195A such as trans-195A,13a,b 4a-epi-Pmiliotoxin
C,13c 2-epi-cis-195A,11a,d,13d are also attractive targets for
lective intramolecular Mannich reaction. The developed synthetic synthetic organic chemists (Figure 1). Asymmetric total
syntheses of trans-219A14 and gephyrotoxin15 have been
accomplished. General strategies for constructing the 2,5-
method could be applied to the catalytic asymmetric synthesis of
(+)-2-epi-cis-195A.
Key word: asymmetric allylic amination, asymmetric synthesis,
chiral diaminophosphine oxide, decahydroquinoline alkaloid, in-
tramolecular Mannich reaction, palladium
disubstituted decahydroquinoline skeleton bearing four
asymmetric carbon centers in an enantioselective manner
would allow access to various decahydroquinoline alka-
loids for unequivocal determination of their ambiguous
molecular structure. Furthermore, new synthetic entries to
functionalized hydroquinolines can be applied to the syn-
thesis of other natural products with a 1-azabicyclo[3.3.0]
skeleton and pharmacologically interesting heterocy-
cles.16,17
Decahydroquinoline ring systems are ubiquitous structur-
al motifs in various biologically active compounds. Since
the first isolation of a representative decahydroquinoline
alkaloid cis-195A (pumiliotoxin C) from skin extracts of
the Panamanian frog dendrobatus pumilio,1 approximate-
ly 50 decahydroquinoline alkaloids have been isolated
from dendrobatide and mantelline frogs,2 bufonid toads,3
tunicates,4 marine flatworms,5 and myrmicine ants.6
Decahydroquinoline alkaloids generally possess a cis- or
trans-fused azabicyclic structure with a side-chain sub-
stituent at both the C-2 and C-5 positions (Figure 1).
These alkaloids, however, cannot be obtained from their
natural sources in sufficient quantities for NMR analysis
and X-ray crystal structure analysis. Therefore, the struc-
ture and stereochemistry of many decahydroquinoline al-
kaloids have been only tentatively assigned based on MS
and IR spectra.7 Some decahydroquinoline alkaloids ex-
hibit neurological activity as reversible antagonists of the
nicotinic acetylcholine receptor channel.8 An inhibitory
effect against sodium and potassium transport has been
also reported.9 These profiles make this class of com-
pounds an attractive target in the field of pharmaceutical
chemistry.
H
H
H
4
5
6
7
3
2
4a
8a
N
N
N1
H
8
H
H
H
H
H
cis-195A
2-epi-cis-195A
H
trans-195A
H
(pumiliotoxin C)
H
N
H
N
N
H
H
H
H
HO
cis-219A
trans-223F
gephyrotoxin
Figure 1 Representative decahydroquinoline alkaloids
An efficient method of introducing an amine unit to six-
membered-ring carbon skeletons in an enantioselective
manner can be a powerful tool for the asymmetric synthe-
sis of decahydroquinoline alkaloids. Since the first report
in 2004,18 we have intensively studied transition-metal-
catalyzed asymmetric allylic substitution using aspartic
acid-derived P-chiral diaminophosphine oxides: DIA-
PHOXs.19 These pentavalent phosphorus compounds,
preligands, are activated in situ by N,O-bis(trimethylsi-
lyl)acetamide (BSA)-induced tautomerization to afford
trivalent phosphorus compounds that function as the actu-
al ligands. The DIAPHOX preligands are effective for Pd-
catalyzed asymmetric allylic substitution of cyclic allylic
carbonates with various amine nucleophiles.20 As shown
in Scheme 1, asymmetric allylic amination of an ester-
Due to the structural diversity and interesting biological
activities of decahydroquinoline alkaloids, extensive ef-
forts have been directed towards the synthesis of these al-
kaloids and their structurally related heterocyclic
compounds. Total synthesis of cis-195A has been most in-
tensively studied since the 1980s. In addition to racemate
syntheses,10 several enantioselective total syntheses have
SYNTHESIS 2011, No. 16, pp 2540–2548
x
x.
x
x
.
2
0
1
1
Advanced online publication: 14.07.2011
DOI: 10.1055/s-0030-1260102; Art ID: E50111SS
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Asymmetric Synthesis of 2-Substituted Hexahydroquinolin-4-ones
2541
conjugated cyclohexenyl carbonate using benzylamine as
a nucleophile gave the corresponding chiral amine in ex-
cellent yield with high enantiomeric purity. The suitably
functionalized structure of the reaction product led us to
investigate catalytic asymmetric synthesis of 2,5-disubsti-
tuted decahydroquinolines. Herein, we describe a new
method of synthesizing 2-substituted hexahydroquinolin-
4-ones as optically active compounds through a Pd-cata-
lyzed asymmetric allylic amination and diastereoselective
intramolecular Mannich reaction sequence, which can be
successfully applied to the catalytic asymmetric synthesis
of (+)-2-epi-cis-195A.
O
O
Pd (cat.)
(S,RP)-1, BSA
OMe
OMe
Ph
HN
N
H
P
O
BnNH2, MeCN
X
NH
N
H
H
(X = OCOOMe)
DIAPHOX
(S,RP)-1
99% yield, 95% ee
Scheme 1 Pd-catalyzed asymmetric allylic amination using chiral
diaminophosphine oxide preligand (S,RP)-1
The synthetic plan for enantioselective synthesis of 2,5-
disubstituted decahydroquinolines is shown in Scheme 2.
Retrosynthetically, 2,5-disubstituted azabicyclic ketone 2
Biographical Sketches
Kazumi Kakugawa was under the direction of Prof. interests include the devel-
born in Chiba, Japan, in Yasumasa Hamada. He is opment of novel methods
1984. He received his B.S. currently a Ph.D. course stu- for the synthesis of hetero-
(2008) and M.S. (2010) de- dent in Prof. Hamada’s cyclic compounds.
grees from Chiba University group. His current research
Tetsuhiro Nemoto was 2003, he started his academ- Award in Synthetic Organic
born in Chiba, Japan, in ic career as an assistant pro- Chemistry (2007), the Phar-
1976. He received his B.S. fessor in Prof. Yasumasa maceutical Society of Japan
(1999), M.S. (2001), and Hamada’s group at Chiba Award for Young Scientists
Ph.D. (2005) degrees from University. He has received (2008), and the Thieme
the University of Tokyo un- the Banyu Award in Syn- Chemistry Journal Award
der the direction of Prof. thetic Organic Chemistry (2011). His current research
Masakatsu Shibasaki. In (2004), Inoue Research interests include asymmet-
2002, he also worked as a Award for Young Scientists ric catalysis and synthetic
JSPS Research Fellow. In (2005),
Daiichi-Sankyo organic chemistry.
Yuta Kohno was born in sity under the direction of Hamada’s group, he started
Chiba, Japan, in 1985. He Prof. Yasumasa Hamada. working in the analytical de-
received his B.S. degree After spending one year as a partment of Tokyo metro-
(2010) from Chiba Univer- graduate student in Prof. politan.
Yasumasa Hamada is Pro- tant professor. After obtain- Pharmaceutical Society of
fessor of Pharmaceutical ing his Ph.D. in 1982 and Japan Award for Young Sci-
Chemistry at Chiba Univer- one year postdoctoral work entists in 1990 and the Phar-
sity. He was born in Hok- with Prof. E. J. Corey at maceutical Society of Japan
kaido in 1949 and received Harvard University in 1985, Award in 2011. His research
his B.S. degree (1973) from he was promoted to associ- interests include the devel-
Toyama University and ate professor at Nagoya City opment of new methods and
M.S. degree (1975) from the University in 1988. In 1995, reagents for use in organic
University of Tokyo. In he moved to Chiba Univer- synthesis and total synthesis
1977, he joined Nagoya sity to take up his present of biologically active natu-
City University as an assis- position. He received the ral products.
Synthesis 2011, No. 16, 2540–2548 © Thieme Stuttgart · New York

2542
K. Kakugawa et al.
FEATURE ARTICLE
would be a reasonable precursor of the target decahydro- saturated ester 10 was converted into the corresponding
quinolines, which, in turn, would be obtained from 3 via a,b-unsaturated aldehyde 11 by a two-step process in-
diastereoselective conjugate addition and protonation. volving diisobutylaluminum hydride (DIBAL-H) reduc-
There is a b-amino ketone motif in the a,b-unsaturated ke- tion, followed by oxidation with Dess–Martin periodinane
tone 3. Therefore, we envisioned that an intramolecular (DMP) (88% yield, 2 steps). Subsequent aldol reaction of
Mannich reaction using d-amino b-keto ester 5 and alde- 11 with lithium ester enolates proceeded smoothly at
hyde 6, followed by a decarboxylation reaction of 4, –78 °C, affording the corresponding adducts 12a and 12b
would be applicable to construct the azabicyclic core in 3. in over 90% yield. Finally, Dess–Martin oxidation of the
Finally, compound 7, a promising precursor of 5, can be alcohol provided d-amino b-keto esters 13a and 13b in
prepared via asymmetric allylic amination of 8 with a 79% and 97% yield, respectively.
flexibly deprotectable amine such as 4-methoxybenzyl-
amine using the Pd-DIAPHOX catalyst system.
(η3-C3H5PdCl)2
(0.05 mol%)
O
O
Boc2O
OMe
(S,RP)-1 (0.2 mol%)
NaI, Et3N
MeCN, r.t.
88%
OMe
R2
5
conjugate
addition &
protonation
R2
O
O
H
H
BSA (3 equiv)
NH
OCOOMe
4-methoxybenzyl-
amine (3 equiv)
MeCN, –35 °C
H
(S)-9
2
8
Ar
N
R1
(3 g scale)
N
P
R1
N
P
R1
(Ar = 4-MeOC6H4)
O
H
H
H
99%, 95% ee
H
2,5-disubstituted
decahydroquinolines
O
O
2
3
1) DIBAL-H
CH2Cl2, –78 °C
OH
O
O
O
H
OR
OMe
OR3
OR3
R1
Boc
2) DMP, Et3N
CH2Cl2, r.t.
LDA
THF, –78 °C
Boc
N
N
H
H
H
R1
decarboxylation
N
P
NH
P
H
H
10
88% (2 steps)
11
Ar
Ar
diastereoselective
intramolecular
Mannich reaction
O
6
OH
O
O
O
4
5
O
O
OR
OR
asymmetric allylic
amination
DMP
OMe
Boc
Boc
OMe
OCOOMe
CH2Cl2, r.t.
N
N
H
H
using Pd-DIAPHOX
catalyst system
NH
P
H
Ar
Ar
7
8
12a R = Me: 90%
12b R = allyl: 97%
13a R = Me: 79%
13b R = allyl: 97%
Scheme 2 Retrosynthetic plan for 2,5-disubstituted decahydroqui-
nolines
Scheme 4 Preparation of d-amino b-keto esters using Pd-catalyzed
asymmetric allylic amination
Considering the structure of compound 4, the stereochem-
istry at the C-2 position is expected to epimerize through
the retro-aza-Michael reaction (Scheme 3). The molecular
energy calculation (M06-2X/6-31G**) of model com-
pounds 4a and 4b revealed that 4b is 2.42 kcal/mol more
stable than 4a, indicating that thermodynamically stable
4b-type adducts would be obtained as the major product.21
With the substrates in hand, the construction of the azabi-
cyclic skeleton through the diastereoselective intramolec-
ular Mannich reaction (Table 1) was next examined. After
removal of the Boc group of 13a under acidic conditions,
the resulting amine trifluoroacetate salt was reacted with
n-butyraldehyde in the presence of sodium bicarbonate
and 3 Å molecular sieves (MS) at room temperature. After
48 hours, the desired azabicyclic compound 15aa was ob-
tained in 79% yield with a 98:2 diastereomeric ratio
(Table 1, entry 1). The same reaction using allyl ester-
type substrate 13b also gave 15ba in 98% yield as a nearly
diastereomerically pure compound (entry 2). On the other
hand, when this reaction was quenched after four hours, a
diastereomeric product mixture was obtained in 52%
yield with a ca. 2:1 ratio, clearly indicating that the prod-
uct ratio of this cyclization process was thermodynamical-
ly controlled (entry 3). Intramolecular Mannich reactions
with some other aldehydes were also examined using 13b
under the same reaction conditions. Primary aldehydes, an
a-branched primary aldehyde, an aromatic aldehyde, and
an a,b-unsaturated aldehyde could be utilized for this pro-
cess, giving the corresponding products in moderate to
high yield with excellent diastereoselectivity (entries 4–
9). NOE experiments revealed that the stereochemistry of
O
O
OH
O
OH
O
OMe
OMe
OMe
NH
Me
H
N
N
H
H
Me
Me
4a
ΔE = 2.42 kcal/mol
4b
Scheme 3 Thermodynamic stability of azabicyclic adducts
Our synthesis began with the preparation of optically ac-
tive d-amino b-keto esters through an asymmetric allylic
amination using the Pd-DIAPHOX catalyst system
(Scheme 4). Using 0.05 mol% of [h3-C3H5PdCl]2, 0.2
mol% of (S,RP)-1, and BSA, asymmetric allylic amination
of 8 with 4-methoxybenzylamine proceeded at –35 °C,
providing the corresponding product (S)-920b in 99% yield
with 95% ee. After protection of the secondary amine with
a tert-butoxycarbonyl (Boc) group (88% yield), a,b-un-
Synthesis 2011, No. 16, 2540–2548 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Synthesis of 2-Substituted Hexahydroquinolin-4-ones
2543
15bb was 2S,8aS, consistent with the computational pre- We next performed decarboxylation of the reaction prod-
diction shown in Scheme 3.22
ucts. Allyl esters are easily transformed to the correspond-
ing carboxylate in the presence of Pd catalyst and amine
nucleophiles. In practice, a deallylation reaction of 15ba
(95% ee)23 proceeded smoothly using 1 mol% of
Pd(PPh3)4 and 10 equivalents of morpholine in THF at
room temperature. After the starting material was con-
sumed, 1 M aqueous HCl was added subsequently to the
reaction mixture to give 2-propylhexahydroquinoline-4-
one (+)-16a (95% ee)23 in 82% yield (Scheme 5).
Table 1 Diastereoselective Intramolecular Mannich Reaction
O
O
OH
N
O
1) TFA–CH2Cl2 (1:1)
Et3SiH (10 equiv), r.t., 30 min
OR1
OR1
2) R2-CHO 14a–g (3 equiv)
NaHCO3, MS 3 Å
Boc
N
R2
H
H
CH2Cl2–MeOH (5:1), r.t., 48 h
Ar
13a,b
Ar
14a: R2 = n-Pr, 14b: R2 = Me
14c: R2 = PhCH2CH2
15
(Ar = 4-MeOC6H4)
Having established the synthetic route to enantiomerically
enriched 2-propylhexahydroquinolin-4-one 16a, our at-
tention was focused next on the enantioselective synthesis
of 2-epi-cis-195A (Scheme 6). As shown in Scheme 1, the
stereochemistry at the C-8a position of cis-195A is R.
Therefore, (2R,8aR)-(–)-16a with 95% ee was first pre-
pared using the developed method, where DIAPHOX pre-
ligand (R,SP)-1 derived from (R)-D-aspartic acid was
utilized in the Pd-catalyzed asymmetric allylic amination
step. Conjugate addition of an organocopper reagent pre-
pared from CuCN and methyllithium (CuCN/MeLi = 1:2)
to (–)-16a, followed by entrapment of the copper enolate
17 with N-(5-chloro-2-pyridyl)bis(trifluoromethansulfon-
imide) (18),24 afforded triflate 19 in 54% yield as a single
diastereomer. When the copper enolate 17 was quenched
with tert-butanol as a proton source, diastereomeric mix-
tures 20 and 21 were obtained in 40% and 56%, respec-
tively. Relative configurations of 20 and 21, determined
by NOE experiments,22 revealed that the conjugate addi-
tion predominantly occurred from the stereoelectronically
preferred b-axial direction of (–)-16a (Re-face attack).22,25
14d: R2 = CH C(CH2)3
14e: R2 = i-Pr, 14f: R2 = Ph
14g: R2 = trans-Me(CH2)2CH=CH
Entry
Substrate Aldehyde Product
Yield (%)a dr
1
2
3c
4
5
6
7
8
9
13a
13b
13b
13b
13b
13b
13b
13b
13b
14a
14a
14a
14b
14c
14d
14e
14f
15aa
15ba
15ba
15bb
15bc
15bd
15be
15bf
15bg
79
98:2
>99:1
67:33
>99:1
>99:1
>99:1
94:6
98 (87)b
52
50
87
66
74
57
98:2
14g
47
97:3
a Yield of diastereomeric mixture.
b Isolated yield for the reaction on a 15.2 g scale.
c Reaction was quenched in 4 h.
Compound 19 can be directly transformed to 2-epi-cis-
195A by treating with hydrogen in the presence of a tran-
sition-metal catalyst through a series of reactions involv-
ing the reductive removal of triflate, diastereoselective
hydrogenation, and the removal of a 4-methoxybenzyl
group. The reductive removal of triflate was, however,
very sluggish under several reaction conditions [Pd/C, H2,
MeOH; Pd(OH)2/C, H2, MeOH–2 M HCl–MeOH;
Pd(OH)2/C, H2 (100 atm), MeOH–2 M HCl–MeOH].
OH
O
O
N
Pd(PPh3)4 (1 mol%)
morpholine (10 equiv)
THF, r.t.
Oallyl
then 1 M aq HCl
(Ar = 4-MeOC6H4)
N
H
H
Ar
15ba (95% ee)
Ar
82%
(+)-16a (95% ee)
Scheme 5 Decarboxylation of 15ba
O
OTf
N
OTf
OCu
N
transition-
metal
then
CuCN
MeLi
2-epi-cis-195A
+
18
catalyst
THF–Et2O
54%
very
sluggish
H2
N
Pr
2-4a-epi-
pumiliotoxin C
Pr
N
H
Pr
Pr
H
H
H
H
(–)-16a
Cl
18
Ar
17
Ar =
4-MeOC6H4
Ar
Ar
N
H
NTf2
19
[ 17 ]
20: 40%
21: 56%
t-BuOH
then
TIPSCl
OTf
N
O
O
N
OTIPS
Pd(OH)2/C, H2
2 M HCl in MeOH
MeOH
LDA
THF
–78 °C
H
H
H
H
TBAF
wet THF
+
then 18
then aq NaHCO3
93%
Pr
N
N
Pr
Pr
N
Pr
20: 27%
21: 70%
H
H
H
H
H
87%
Ar
Ar
Ar
Ar
(+)-2-epi-cis-195A
22
20
21
23
Scheme 6 Asymmetric synthesis of (+)-2-epi-cis-195A
Synthesis 2011, No. 16, 2540–2548 © Thieme Stuttgart · New York

2544
K. Kakugawa et al.
FEATURE ARTICLE
under reduced pressure. The obtained crude residue was purified by
flash column chromatography to give (S)-9 (3.94 g, 14.3 mmol,
99%) as a pale yellow oil; [a]D23 –60.9 (c 1.40, CHCl3); 95% ee. The
enantiomeric excess was determined by chiral HPLC analysis after
converting into the corresponding tert-butyl carbamate 10
{DAICEL CHIRALPAK AD-H, hexane–propan-2-ol, 97:3, flow
rate: 0.5 mL/min, tR 32.1 min [(R)-isomer] and 38.3 min [(S)-iso-
mer], detection at 254 nm}.
Therefore, the synthetic route was changed to that using
compound 21 as the key intermediate. Although the reac-
tion was quenched with various proton donors to improve
the isolate yield of 21 from 17, all trials gave less satisfac-
tory results.22 On the other hand, the diastereoselective
protonation proceeded with improved efficiency using the
corresponding enol triisopropylsilyl (TIPS) ether 22. Af-
ter conversion of 17 into compound 22 by trapping with
TIPSCl, the copper species was removed from the reac-
tion mixture by washing with ammonia solution. The ob-
tained crude 22 was allowed to react with
tetrabutylammonium fluoride (TBAF) in THF at room
temperature, affording compound 21 in 70% yield, ac-
(6S)-6-[tert-Butoxycarbonyl-(4-methoxybenzyl)amino]cyclo-
hex-1-enecarboxylic Acid Methyl Ester (10)
To a solution of 9 (180.2 mg, 0.654 mmol), Et3N (0.28 mL, 2.00
mmol), and NaI (98.1 mg, 0.654 mmol) in MeCN (3.3 mL) at 0 °C
was added Boc2O (214.3 mg, 0.981 mmol), and the reaction mixture
was stirred at r.t. After 12 h, the reaction was quenched with H2O
companied by the formation of 20 in 27% yield. Com- (3.3 mL), and the resulting mixture was extracted with EtOAc (3 ×
5 mL). The combined organic layers were washed with brine (5 mL)
and dried (Na2SO4). After concentration in vacuo, the obtained res-
pound 21 was then converted into the corresponding enol
triflate 23 by treatment with lithium diisopropylamide
(LDA), followed by the addition of 18 (87% yield). Final-
ly, compound 23 was reacted in the presence of Pearl-
idue was purified by flash column chromatography to give 10
(215.5 mg, 0.573 mmol, 88%) as a pale yellow oil; [a]D23 –37.6 (c
3.10, CHCl3); 95% ee.
man’s catalyst under a hydrogen atmosphere, providing
IR (ATR): 2946, 1716, 1684, 1511, 1241, 1162, 1035, 817, 761
22
(+)-2-epi-cis-195A in 93% yield {[a]D +18.1 (c 0.25,
MeOH)}. The NMR data were identical to the data previ-
ously reported in the literature for ent-2-epi-cis-195A:
[a]D22 –22.2 (c 0.6, MeOH).11d,13d
cm–1.
1H NMR (CDCl3, 55 °C): d = 1.41 (s, 9 H), 1.40–1.90 (m, 4 H),
2.10–2.20 (m, 2 H), 3.64 (s, 3 H), 3.50–3.90 (m, 2 H), 3.79 (s, 3 H),
4.23 (d, J = 14.4 Hz, 1 H), 6.75–6.85 (m, 2 H), 6.95–7.25 (m, 3 H).
In conclusion, we have developed a novel method to syn-
thesize 2-substituted hexahydroquinolin-4-one deriva-
tives through asymmetric allylic amination using the Pd-
DIAPHOX catalyst system and diastereoselective in-
tramolecular Mannich reaction sequence. The present
method was successfully applied to enantioselective syn-
thesis of (+)-2-epi-cis-195A in combination with a diaste-
reoselective conjugate addition of an organocopper
reagent (33% overall yield in 12 steps from compound 8).
The divergent synthetic route provides access to natural
products with the same stereochemical arrangement, such
as cis-219A and gephyrotoxin. Further studies on the ap-
plication of the developed method to catalytic asymmetric
synthesis of other natural products are in progress.
13C NMR (CDCl3, 55 °C): d = 19.9, 25.5, 28.3 (3 C), 28.8, 48.5,
51.3, 51.7, 55.2, 79.5, 113.6 (2 C), 128.2 (2 C), 132.0, 141.8, 143.2,
155.6, 158.5, 166.9.
ESI-HRMS: m/z calcd for C21H29NO5 + Na (M + Na+): 398.1943;
found: 398.1935.
(1S)-(2-Formylcyclohex-2-enyl)(4-methoxybenzyl)carbamic
Acid tert-Butyl Ester (11)
To a solution of 10 (1.20 g, 3.20 mmol) in CH2Cl2 (32 mL) at
–78 °C was added DIBAL-H (9.60 mL, 1.0 M in n-hexane, 9.60
mmol), and the reaction mixture was stirred at the same tempera-
ture. After 30 min, the reaction was quenched by the addition of
MeOH (6 mL) and H2O (32 mL), and the resulting mixture was ex-
tracted CH2Cl2 (3 × 30 mL). The combined organic layers were
dried (MgSO4). After concentration in vacuo, the obtained residue
was purified by flash column chromatography to give the corre-
27
sponding alcohol (1.02 g, 2.95 mmol, 92%) as a colorless oil; [a]D
–68.2 (c 1.47, CHCl3, 95% ee).
IR spectra were recorded on a JASCO FT/IR 230 Fourier transform
IR spectrophotometer, equipped with ATR (Smiths Detection,
DuraSample IR II). NMR spectra were recorded on a JEOL ecp 400
Intermediate Alcohol
spectrometer, operating at 400 MHz for 1H NMR, 100 MHz for 13
C
IR (ATR): 2934, 1668, 1612, 1512, 1405, 1365, 1244, 1160, 1035,
976, 734, 701 cm–1.
NMR. Optical rotations were measured on a JASCO P-1020 pola-
rimeter. ESI mass spectra were measured on JEOL AccuTOF LC-
plus JMS-T100LP. The enantiomeric excesses were determined by
HPLC analysis. HPLC was performed on JASCO HPLC systems
consisting of the following: pump, PU-980; detector, UV-970, mea-
sured at 254 nm. Reactions were carried out in anhydrous solvents.
Other reagents were purified by the usual methods.
1H NMR (CDCl3, 55 °C): d = 1.42 (s, 9 H), 1.35–1.85 (m, 4 H),
1.94–2.05 (m, 2 H), 2.71 (br s, 1 H), 3.78 (s, 3 H), 3.72–3.85 (m, 2
H), 3.93 (d, J = 14.2 Hz, 1 H), 3.90–4.10 (m, 1 H), 4.46 (d, J = 14.2
Hz, 1 H), 5.85–5.95 (m, 1 H), 6.77–6.90 (m, 2 H), 7.09–7.21 (m, 2
H).
13C NMR (CDCl3, 55 °C): d = 21.6, 24.8, 28.1, 28.3 (3 C), 47.6,
52.9, 55.2, 64.6, 80.2, 113.8 (2 C), 127.9, 128.9, 131.8 (2 C), 137.8,
156.9, 158.6.
6-Methoxycarbonyloxycyclohex-1-enecarboxylic acid methyl ester
(8) was prepared according to the literature procedure.20b,26
ESI-HRMS: m/z calcd for C20H29NO4 + Na (M + Na+): 370.1994;
found: 370.2008.
(6S)-6-(4-Methoxybenzylamino)cyclohex-1-enecarboxylic Acid
Methyl Ester (9)20b
To a solution of [h3-C3H5PdCl]2 (2.7 mg, 0.0072 mmol), (S,RP)-1
(11.3 mg, 0.028 mmol), and 8 (3.06 g, 14.4 mmol) in MeCN (72
mL) at r.t. was added BSA (10.7 mL, 43.2 mmol). After stirring the
solution at r.t. for 10 min, and then at –40 °C for 30 min, 4-meth-
oxybenzylamine (5.6 mL, 43.2 mmol) was added to the reaction
mixture over 30 min. After stirring at –35 °C for 48 h, the resulting
mixture was allowed to warm to r.t., and the solvent was removed
To a solution of the obtained alcohol (147.7 mg. 0.425 mmol) and
Et3N (0.24 mL, 1.70 mmol) in CH2Cl2 (4.3 mL) was added Dess–
Martin periodinane (360.6 mg, 0.85 mmol), and the resulting mix-
ture was stirred for 4 h at r.t. The reaction was quenched with aq
Na2S2O3 (10 mL), and then Et2O (4.3 mL) was added to the reaction
mixture. After stirring for 1 h, the resulting mixture was extracted
Synthesis 2011, No. 16, 2540–2548 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Synthesis of 2-Substituted Hexahydroquinolin-4-ones
2545
with EtOAc (10 mL), and the combined organic layers were washed
with brine (10 mL) and dried (Na2SO4). After concentration in vac-
uo, the obtained residue was purified by flash chromatography to
give 11 (140.3 mg, 0.406 mmol, 96%) as a yellow oil; [a]D27 –13.7
(c 4.40, CHCl3); 95% ee.
IR (ATR): 2936, 1742, 1681, 1511, 1456, 1402, 1364, 1301, 1242,
1162, 1034, 986 cm–1.
1H NMR (CDCl3, 55 °C): d = 1.42 (s, 9 H), 1.40–1.55 (m, 1 H),
1.55–1.70 (m, 2 H), 1.71–1.87 (m, 1 H), 2.10–2.27 (m, 2 H), 3.35–
3.52 (m, 1 H), 3.64 (d, J = 15.2 Hz, 1 H), 3.78 (s, 3 H), 4.19 (d,
J = 15.2 Hz, 1 H), 4.31–4.50 (m, 1 H), 4.55–4.70 (m, 2 H), 4.70–
4.79 (m, 1 H), 5.15–5.39 (m, 2 H), 5.80–6.00 (m, 1 H), 6.72–6.85
(m, 2 H), 6.85–6.94 (m, 1 H), 7.05–7.18 (m, 2 H).
13C NMR (CDCl3, 55 °C): d = 19.6, 25.6, 28.2 (3 C), 44.7, 49.4,
51.7, 55.0, 65.4, 79.4, 87.2, 113.5 (2 C), 118.1, 128.4, 131.5, 131.7
(2 C), 139.9, 142.9, 155.2, 158.4, 166.9, 192.1.
11
IR (ATR): 2935, 1683, 1511, 1455, 1402, 1364, 1300, 1243, 1163,
1118, 1034 cm–1.
1H NMR (CDCl3, 55 °C): d = 1.43 (s, 9 H), 1.40–1.60 (m, 1 H),
1.65–1.90 (m, 3 H), 2.25–2.35 (m, 2 H), 3.79 (s, 3 H), 4.25 (d,
J = 15.2 Hz, 1 H), 4.20–4.80 (m, 2 H), 6.75–6.90 (m, 3 H), 7.10–
7.20 (m, 2 H), 9.36 (s, 1 H).
13C NMR (CDCl3, 55 °C): d = 20.5, 26.1, 28.1, 28.4 (3 C), 49.8,
51.5, 55.1, 79.6, 113.6 (2 C), 128.6 (2 C), 131.7, 141.4, 155.4,
158.6, 175.6, 192.0.
ESI-HRMS: m/z Calcd for C25H33NO6 + Na (M + Na+): 466.2206;
found: 466.2185.
(2S,8aS)-4-Hydroxy-1-(4-methoxybenzyl)-2-propyl-
1,2,6,7,8,8a-hexahydroquinoline-3-carboxylic Acid Allyl Ester
(15ba)
ESI-HRMS: m/z calcd for C20H27NO4 + Na (M + Na+): 368.1838;
found: 368.1819.
To a solution of 13b (718.5 mg, 1.62 mmol) and Et3SiH (2.59 mL,
16.2 mmol) in CH2Cl2 (8.1 mL) at r.t. was added TFA (8.1 mL), and
the reaction mixture was stirred at the same temperature for 30 min.
After concentration in vacuo, the obtained residue was dissolved in
CH2Cl2 (13.5 mL) and MeOH (2.7 mL). n-Butyraldehyde (14a;
0.44 mL, 4.86 mmol), MS 3Å (0.81 g), and NaHCO3 (408.3 mg,
4.86 mmol) were added to the solution, and the reaction mixture
was stirred at r.t. After 48 h, the resulting mixture was filtered
through a short pad of Celite, and the filtrate was concentration in
vacuo. The obtained residue was purified by flash column chroma-
tography to give 15ba (631.8 mg, 1.59 mmol, 98%) as a yellow oil.
The enantiomeric excess was determined by chiral HPLC analysis
{DAICEL CHIRALPAK AD-H, hexane–propan-2-ol, 99:1, flow
rate: 1 mL/min, tR 9.6 min [(2S,8aS)-isomer] and 11.0 min
3-{(6S)-6-[tert-Butoxycarbonyl(4-methoxybenzyl)amino]cyclo-
hex-1-enyl}-3-hydroxypropionic Acid Allyl Ester (12b)
To a solution of i-Pr2NH (3.5 mL, 25.0 mmol) in THF (54 mL) at
–78 °C was added n-BuLi (16.2 mL, 1.56 M in n-hexane, 25.3
mmol), and the reaction mixture was stirred at the same tempera-
ture. After 30 min, allyl acetate (2.7 mL, 25.0 mmol) was added to
the solution, and the resulting mixture was stirred for additional 30
min at the same temperature. Then, a THF solution of 11 (2.91 g,
8.44 mmol in 30 mL of THF) was added to the mixture, which was
kept stirring at –78 °C. After 12 h, the mixture was quenched with
aq NH4Cl (30 mL), and the resulting mixture was extracted with
EtOAc (3 × 30 mL). The combined organic layers were washed with
brine (30 mL) and dried (Na2SO4). After concentration in vacuo, the
obtained residue was purified by flash column chromatography to
give 12b (3.65 g, 8.19 mmol, 97%) as a mixture of diastereomers
(yellow oil); [a]D23 +4.3 (c 3.85, CHCl3); 95% ee.
23
[(2R,8aR)-isomer], detection at 254 nm}; [a]D +44.3 (c 2.01,
CHCl3); 95% ee.
IR (ATR): 2933, 1649, 1628, 1583, 1509, 1321, 1287, 1239, 1222,
1117, 1073, 1037, 984, 964, 802 cm–1.
IR (ATR): 2933, 1735, 1683, 1512, 1455, 1404, 1365, 1274, 1244,
1158, 1118, 1033, 981 cm–1.
1H NMR (CDCl3): d = 0.76 (t, J = 7.0 Hz, 3 H), 1.17–1.70 (m, 6 H),
1.79–1.91 (m, 2 H), 2.19–2.30 (m, 2 H), 3.14 (d, J = 14.0 Hz, 1 H),
3.43 (dd, J = 3.4, 10.2 Hz, 1 H), 3.73 (d, J = 14.0 Hz, 1 H), 3.80 (s,
3 H), 3.82–3.93 (m, 1 H), 4.58–4.70 (m, 2 H), 5.12–5.30 (m, 2 H),
5.79–5.94 (m, 1 H), 6.73–6.89 (m, 3 H), 7.18–7.26 (m, 2 H), 12.1
(s, 1 H).
13C NMR (CDCl3): d = 13.8, 19.8, 21.9, 26.4, 27.2, 35.4, 51.0, 51.1,
55.2, 55.7, 64.6, 98.9, 113.3 (2 C), 117.5, 128.8, 129.5 (2 C), 132.0,
132.1, 133.2, 158.2, 163.6, 172.5.
1H NMR (CDCl3, 55 °C): d (major diastereomer) = 1.40 (s, 9 H),
1.20–1.50 (m, 1 H), 1.50–1.70 (m, 2 H), 1.75–1.85 (m, 1 H), 1.95–
2.05 (m, 2 H), 2.40 (br s, 1 H), 2.60–3.00 (m, 2 H), 3.78 (s, 3 H),
4.04 (d, J = 15.6 Hz, 1 H), 4.27–4.37 (m, 1 H), 4.49 (d, J = 15.6 Hz,
1 H), 4.50–4.65 (m, 2 H), 4.65–4.80 (m, 1 H), 5.22 (dd, J = 1.2, 10.4
Hz, 1 H), 5.31 (dd, J = 1.2, 17.2 Hz, 1 H), 5.80–6.00 (m, 1 H), 6.05–
6.16 (m, 1 H), 6.77–6.88 (m, 2 H), 7.10–7.20 (m, 2 H).
13C NMR (CDCl3, 55 °C): d (major diastereomer) = 21.2, 24.8, 28.4
(3 C), 28.8, 41.3, 47.5, 53.2, 55.3, 65.2, 67.4, 80.2, 113.8 (2 C),
118.3, 126.9, 127.9, 131.9, 132.1 (2 C), 138.6, 156.2, 158.6, 172.2.
ESI-HRMS: m/z calcd for C24H32NO4 (M + H+): 398.2331; found:
398.2336.
ESI-HRMS: m/z calcd for C25H35NO6 + Na (M + Na+): 468.2362;
found: 468.2341.
(2S,8aS)-1-(4-Methoxybenzyl)-2-propyl-2,3,6,7,8,8a-hexahy-
dro-1H-quinolin-4-one [(+)-16a]
To a solution of 15ba (1.41 g, 3.55 mmol) and morpholine (3.1 mL,
35.5 mmol) in THF (36 mL) at r.t. was added Pd(PPh3)4 (41.1 mg,
0.0355 mmol), and the resulting mixture was stirred at the same
temperature. After 2 h, 1 M aq HCl (36 mL) was added to the solu-
tion, and the resulting mixture was stirred at r.t. for additional 24 h.
After the reaction was quenched with aq NaHCO3 (50 mL), the ob-
tained mixture was extracted with EtOAc (3 × 50 mL). The com-
bined organic layers were washed with brine (50 mL), and dried
(Na2SO4). After concentration in vacuo, the obtained residue was
purified by flash column chromatography to give (+)-16a (910.9
mg, 2.91 mmol, 82%) as a yellow oil. The enantiomeric excess was
determined by chiral HPLC analysis {DAICEL CHIRALPAK AD-
H, hexane–propan-2-ol, 99:1, flow rate: 1 mL/min, tR 19.5 min
[(2S,8aS)-isomer] and 22.9 min [(2R,8aR)-isomer], detection at 254
nm}; [a]D25 +9.9 (c 1.22, CHCl3); 95% ee.
3-{(6S)-6-[tert-Butoxycarbonyl(4-methoxybenzyl)amino]cyclo-
hex-1-enyl}-3-oxopropionic Acid Allyl Ester (13b)
To a solution of 12b (3.45 g, 7.74 mmol) in CH2Cl2 (77.4 mL) at r.t.
was added Dess–Martin periodinane (3.61 g, 8.51 mmol), and the
reaction mixture was stirred at the same temperature. After 12 h, the
reaction was quenched by the addition of aq Na2S2O3 (40 mL) and
sat. aq NaHCO3 (40 mL) After dilution with Et2O (40 mL), the re-
sulting mixture was stirred for 1 h, and then extracted with EtOAc
(3 × 100 mL). The combined organic layers were washed with brine
(100 mL) and dried (Na2SO4). After concentration in vacuo, the ob-
tained residue was purified by flash column chromatography to give
13b (3.33 g, 7.51 mmol, 97%) as a pale yellow oil; [a]D23 –39.9 (c
1.45, CHCl3); 95% ee.
Synthesis 2011, No. 16, 2540–2548 © Thieme Stuttgart · New York

2546
K. Kakugawa et al.
FEATURE ARTICLE
IR (ATR): 2930, 1686, 1613, 1509, 1457, 1298, 1241, 1170, 1101,
1034, 830, 807, 731 cm–1.
purified by flash column chromatography to give 20 (13.5 mg,
0.0410 mmol, 40%) and 21 (19.0 mg, 0.0577 mmol, 56%).
1H NMR (CDCl3): d = 0.85 (t, J = 7.0 Hz, 3 H), 1.15–1.73 (m, 6 H),
1.77–1.89 (m, 1 H), 1.93–2.08 (m, 1 H), 2.16–2.28 (m, 2 H), 2.33
(dd, J = 3.0, 17.2 Hz, 1 H), 2.60 (dd, J = 6.4, 17.2 Hz, 1 H), 2.90–
3.02 (m, 1 H), 3.55–3.70 (m, 1 H), 3.67 (d, J = 14.0 Hz, 1 H), 3.73
(d, J = 14.0 Hz, 1 H), 3.81 (s, 3 H), 6.79–6.90 (m, 3 H), 7.24–7.33
(m, 2 H).
13C NMR (CDCl3): d = 14.1, 19.8, 21.1, 26.1, 28.2, 31.6, 42.2, 52.2,
54.3, 54.5, 55.2, 113.6 (2 C), 129.3 (2 C), 132.3, 137.1, 137.4,
158.5, 199.6.
Method B
To a suspension of CuI (1.41 g, 7.40 mmol) in THF (34.2 mL) at
–78 °C was added MeLi (14.8 mL, 1.0 M in Et2O, 14.8 mmol), and
the resulting mixture was stirred at the same temperature. After 30
min, triisopropylsilyl chloride (1.6 mL, 7.47 mmol) was added to
the solution, and the reaction mixture was stirred at the same tem-
perature for additional 30 min. A THF solution of (–)-16a (979.6
mg, 2.46 mmol in 15 mL of THF) was added to the solution. The
reaction mixture was stirred for 30 min at –78 °C, and then gradu-
ally warmed to r.t. After stirring overnight, the reaction was
quenched with sat. aq NaHCO3 (40 mL) and the resulting mixture
was stirred for 1 h at r.t. A small volume of ammonia solution was
added to the suspension to dissolve the solidified copper species.
(Caution! If a large volume of ammonia solution was added to the
suspension, enol silyl ether 22 was converted into 20 rather than
21.) The resulting mixture was extracted with EtOAc (3 × 40 mL).
The combined organic layers were washed with brine (40 mL) and
dried (Na2SO4). After concentration in vacuo, the obtained residue
was dissolved in wet (reagent grade) THF (16 mL). TBAF (8.6 mL,
1.0 M in THF, 8.6 mmol) was added to the solution, and the result-
ing mixture was stirred for 24 h at r.t. The reaction was quenched
with H2O (20 mL) and extracted with EtOAc (3 × 20 mL). The com-
bined organic layers were washed with brine (20 mL), and dried
(Na2SO4). After concentration in vacuo, the obtained crude residue
was purified by flash column chromatography to give 20 (215.1 mg,
0.653 mmol, 27%) and 21 (566.9 mg, 1.72 mmol, 70%).
ESI-HRMS: m/z calcd for C20H27NO2 + Na (M + Na+): 336.1940;
found: 336.1963.
(2R,5R,8aR)-Trifluoromethanesulfonic Acid 1-(4-Methoxyben-
zyl)-5-methyl-2-propyl-1,2,3,5,6,7,8,8a-octahydroquinolin-4-yl
Ester (19)
To a suspension of CuCN (83.2 mg, 0.927 mmol) in Et2O (3.3 mL)
at –78 °C was added MeLi (1.7 mL, 1.07 M in Et2O, 1.89 mmol),
and the mixture was stirred at the same temperature. After 30 min,
a THF solution of (–)-16a (97.0 mg, 0.309 mmol in 5.0 mL of THF)
was added to the solution, and the resulting mixture was stirred at
the same temperature for 30 min. After gradually warming to r.t.,
the reaction mixture was stirred overnight, and then cooled down to
–78 °C again. N-(5-Chloro-2-pyridyl)bis(trifluoromethanesulfon-
imide) (18; 364.6 mg, 0.928 mmol) was added to the solution. The
reaction was gradually warmed to r.t., and kept stirring overnight.
The reaction was quenched with ammonia solution (10 mL), and the
aqueous phase was extracted with EtOAc (3 × 10 mL). The com-
bined organic layers were washed with brine (10 mL), and dried
(Na2SO4). After concentration in vacuo, the obtained crude residue
was purified by flash column chromatography to give 19 (76.5 mg,
0.166 mmol, 54%) as a pale yellow oil; [a]D24 + 5.4 (c 1.01, CHCl3).
(2R,4aR,5R,8aR)-1-(4-Methoxybenzyl)-5-methyl-2-propyloc-
tahydroquinolin-4-one (20)
Pale yellow oil; [a]D25 –7.5 (c 0.86, CHCl3).
IR (ATR): 2929, 2862, 1703, 1611, 1509, 1459, 1300, 1243, 1169,
1147, 1087, 1035, 822 cm–1.
IR (ATR): 2933, 1510, 1410, 1242, 1203, 1139, 1092, 1038, 966,
928, 903, 870, 837 cm–1.
1H NMR (CDCl3): d = 0.81 (t, J = 7.2 Hz, 3 H), 0.97 (d, J = 7.2 Hz,
3 H), 1.10–1.65 (m, 9 H), 1.91–1.99 (m, 1 H), 2.13 (dd, J = 2.0, 14.8
Hz, 1 H), 2.18 (dd, J = 3.6, 10.4 Hz, 1 H), 2.48–2.57 (m, 1 H), 2.62
(dd, J = 6.0, 14.8 Hz, 1 H), 2.92–3.00 (m, 1 H), 3.14 (dt, J = 3.1,
11.2 Hz, 1 H), 3.74 (d, J = 14.0 Hz, 1 H), 3.81 (d, J = 14.0 Hz, 1 H),
3.81 (s, 3 H), 6.83–6.88 (m, 2 H), 7.26–7.30 (m, 2 H).
1H NMR (CDCl3): d = 0.93 (t, J = 7.2 Hz, 3 H), 1.03 (d, J = 7.2 Hz,
3 H), 1.40–1.70 (m, 9 H), 1.71–1.82 (m, 1 H), 2.10–2.23 (m, 1 H),
2.32 (dd, J = 8.8, 16.0 Hz, 1 H), 2.97–3.09 (m, 1 H), 3.10–3.21 (m,
2 H), 3.28 (d, J = 13.4 Hz, 1 H), 3.66 (d, J = 13.4 Hz, 1 H), 3.81 (s,
3 H), 6.80–6.92 (m, 2 H), 7.18–7.30 (m, 2 H).
13C NMR (CDCl3): d = 13.8, 14.0, 19.6, 20.3, 27.1, 32.2, 32.5, 32.8,
42.6, 50.9, 52.9, 55.2, 55.2, 56.7, 113.6 (2 C), 129.3 (2 C), 132.7,
158.5, 210.4.
ESI-HRMS: m/z calcd for C21H32NO2 (M + H+): 330.2433; found:
330.2448.
13C NMR (CDCl3): d = 13.9, 17.2, 19.8, 20.2, 29.6, 30.0, 32.5, 32.7,
33.8, 49.4, 52.9, 55.2, 55.3, 113.7 (2 C), 118.4 (q, J = 317.6 Hz),
129.4 (2 C), 132.0, 135.0, 137.5, 158.5.
ESI-HRMS: m/z calcd for C22H31F3NO4S (M + H+): 462.1926;
found: 462.1929.
(2R,4aS,5R,8aR)-1-(4-Methoxybenzyl)-5-methyl-2-propyloc-
tahydroquinolin-4-one (21)
Procedures for the Conjugate Addition of Organocopper Re-
agents to Enone (–)-16a
Method A
Pale yellow oil; [a]D24 +27.3 (c 0.88, CHCl3).
To a suspension of CuCN (27.6 mg, 0.308 mmol) in Et2O (1.1 mL)
at –78 °C was added MeLi (0.57 mL, 1.09 M in Et2O, 0.62 mmol),
and the resulting mixture was stirred at the same temperature. After
30 min, a THF solution of (–)-16a (32.2 mg, 0.103 mmol in THF 1.7
mL) was added to the solution, and the reaction was stirred at
–78 °C for 30 min. After gradually warming to r.t., the reaction mix-
ture was stirred overnight. The reaction was quenched with tert-bu-
tyl alcohol (1.7 mL), and the mixture was stirred for additional 30
min. Ammonia solution (5 mL) was added to the mixture and the
aqueous layer was extracted with EtOAc (3 × 10 mL). The com-
bined organic layers were washed with brine (10 mL), and dried
(Na2SO4). After concentration in vacuo, the obtained residue was
IR (ATR): 2926, 2855, 1701, 1509, 1457, 1376, 1301, 1241, 1173,
1095, 1035, 828 cm–1.
1H NMR (CDCl3): d = 0.81 (d, J = 7.2 Hz, 3 H), 0.88 (t, J = 7.0 Hz,
3 H), 1.10–1.75 (m, 10 H), 2.23 (dd, J = 8.0, 13.4 Hz, 1 H), 2.25–
2.35 (m, 1 H), 2.39 (dd, J = 4.0, 13.4 Hz, 1 H), 2.45–2.57 (m, 1 H),
3.05–3.21 (m, 2 H), 3.62 (d, J = 13.4 Hz, 1 H), 3.80 (d, J = 13.4 Hz,
1 H), 3.82 (s, 3 H), 6.81–6.95 (m, 2 H), 7.26–7.35 (m, 2 H).
13C NMR (CDCl3): d = 14.1, 18.6, 19.4, 20.4, 27.6, 28.1, 30.4, 32.4,
44.0, 49.2, 55.1, 55.2, 55.2, 55.6, 113.7 (2 C), 129.3 (2 C), 132.1,
158.5, 212.0.
ESI-HRMS: m/z calcd for C21H32NO2 (M + H+): 330.2433; found:
330.2448.
Synthesis 2011, No. 16, 2540–2548 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Synthesis of 2-Substituted Hexahydroquinolin-4-ones
2547
(2R,4aS,5R,8aR)-Trifluoromethanesulfonic Acid 1-(4-Methoxy-
benzyl)-5-methyl-2-propyl-1,2,4a,5,6,7,8,8a-octahydroquino-
lin-4-yl Ester (23)
Acknowledgment
This work was supported in part by Grant-in Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan. We thank Mr. Takashi Fukuyama and Ms.
Ruriko Hayasaki for their contributions in the early stage of this
work. We also thank Dr. Ryo Takita at the University of Tokyo for
his kind support with DFT calculations.
To a solution of i-Pr2NH (0.20 mL, 1.43 mmol) in THF (7.0 mL) at
–78 °C was added n-BuLi (0.91 mL, 1.56 M in n-hexane, 1.42
mmol), and the reaction mixture was stirred at the same tempera-
ture. After 30 min, a THF solution of 21 (232.7 mg, 0.706 mmol in
4.0 mL of THF) was added to the solution, and the mixture was
stirred at –78 °C. After 1 h, 18 (831.7 mg, 2.12 mmol) was added to
the solution, and the resulting mixture was stirred at the same tem-
perature for 30 min. After gradually warming to r.t., the mixture was
stirred overnight, and quenched with ammonia solution (10 mL).
The aqueous phase was extracted with EtOAc (3 × 15 mL) and the
combined organic layers were washed with brine (20 mL) and dried
(Na2SO4). After concentration in vacuo, the obtained crude residue
was purified by flash column chromatography to give 23 (283.0 mg,
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(c) Wright, A. D.; Goclik, E.; König, G. M.; Kaminsky, R.
J. Med. Chem. 2002, 45, 3067.
24
0.613 mmol, 87%) as a pale yellow oil; [a]D –44.8 (c 1.03,
CHCl3).
IR (ATR): 2934, 1510, 1459, 1415, 1244, 1203, 1170, 1140, 1084,
1036, 948, 906, 853 cm–1.
1H NMR (CDCl3): d = 0.86 (d, J = 7.2 Hz, 3 H), 0.88 (t, J = 7.0 Hz,
3 H), 1.15–1.57 (m, 7 H), 1.60–1.72 (m, 2 H), 2.22–2.35 (m, 1 H),
2.49–2.60 (m, 1 H), 2.95–3.05 (m, 1 H), 3.28–3.36 (m, 1 H), 3.41–
3.55 (m, 1 H), 3.77–3.83 (m, 4 H), 3.85 (d, J = 13.6 Hz, 1 H), 5.64–
5.66 (m, 1 H), 6.80–6.93 (m, 2 H), 7.18–7.26 (m, 2 H).
13C NMR (CDCl3): d = 14.4, 17.4, 18.3, 19.0, 19.7, 28.3, 28.7, 34.1,
45.3, 51.0, 51.5, 55.0, 55.1, 113.7 (2 C), 118.6 (q, J = 318.9 Hz),
121.3, 129.0 (2 C), 131.6, 149.5, 158.5.
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Andersen, R. J. Tetrahedron Lett. 1995, 36, 6189.
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Tokuyama, T.; Torres, J. A.; Snelling, R. R.; Jones, T. H.
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Neurochem. Res. 1991, 16, 1207.
ESI-HRMS: m/z calcd for C22H31F3NO4S (M + H+): 462.1926;
found: 462.1933.
(+)-2-epi-cis-195A
To a solution of 23 (35.1 mg, 0.076 mmol) in MeOH (1.5 mL) and
2 M HCl–MeOH (0.076 mL) was added Pd(OH)2/C (7.5 mg, 20
wt% Pd on carbon), and the reaction mixture was stirred under an
H2 atmosphere at r.t. After 24 h, the resulting mixture was filtered
through a short pad of Celite, and the filtrate was evaporated under
reduced pressure. The obtained crude residue was purified by flash
column chromatography to give (+)-2-epi-cis-195A·HCl. The pure
(+)-2-epi-cis-195A·HCl was dissolved in EtOAc (1.6 mL) and sat.
aq NaHCO3 (1.6 mL) was added to the solution. The resulting mix-
ture was stirred at r.t. for 30 min. The aqueous phase was extracted
with EtOAc (3 × 5 mL). The combined organic layers were washed
with brine (10 mL) and dried (Na2SO4). Evaporation of the organic
solvent gave pure (+)-2-epi-cis-195A (13.7 mg, 0.0701 mmol, 93%)
as pale brown oil; [a]D22 +18.1 (c 0.25, MeOH).
(9) Warnick, J. E.; Jessup, P. J.; Overman, L. E.; Eldefrawi, M.
E.; Nimit, Y.; Daly, J. W.; Albuquerque, E. X. Mol.
Pharmacol. 1982, 22, 565.
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7873; and references cited therein. (b) Girard, N.; Hurvois,
J.-P.; Moinet, C.; Toupet, L. Eur. J. Org. Chem. 2005, 2269.
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Chem. Int. Ed. 2008, 47, 3348. (c) Lauzon, S.; Tremblay, F.;
Gagnon, D.; Godbout, C.; Chabot, C.; Mercier-Shanks, C.;
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IR (ATR): 2926, 2871, 1457, 1379, 1287, 1238, 1163, 1029 cm–1.
1H NMR (CDCl3) d = 0.91 (t, J = 6.6 Hz, 3 H), 1.00 (d, J = 7.2 Hz,
3 H), 1.08–1.90 (m, 16 H), 2.85–3.00 (m, 1 H), 2.95 (br s, 1 H), 3.21
(dt, J = 3.9, 10.8 Hz, 1 H).
13C NMR (CDCl3): d = 14.1, 19.2, 19.2, 20.3, 24.9, 27.5, 28.1, 30.6,
32.5, 37.6, 41.3, 49.8, 50.3.
ESI-HRMS: m/z calcd for C13H26N (M + H+): 196.2065; found:
196.2048.
Supporting Information for this article is available online at
http://www.thiem-connect.com/ejournal/toc/synthesis.
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Synthesis 2011, No. 16, 2540–2548 © Thieme Stuttgart · New York

2548
K. Kakugawa et al.
FEATURE ARTICLE
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(22) See Supporting Information for details.
(23) The enantiomeric excess was determined by chiral HPLC
analysis.
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Synthesis 2011, No. 16, 2540–2548 © Thieme Stuttgart · New York