Asymmetric total synthesis of (?)-javaberine A and (?)-epi-javaberine A based on catalytic intramolecular hydroamination of N-methyl-2-(2-styrylaryl)ethylamine

Article abstract of DOI:10.1016/j.tet.2021.132165

Asymmetric total synthesis of (?)-javaberine A and its epimer was achieved by utilizing two methods for isoquinoline synthesis, asymmetric hydroamination of N-methyl-2-(2-styrylaryl)ethylamine and Bischler-Napieralski cyclization. Intramolecular asymmetric hydroamination of N-methyl aminoalkene 4 was catalyzed by lithium amide–chiral bisoxazoline to give tetrahydroisoquinoline (S)-laudanosine with good enantioselectivity in excellent yield. N-Demethylation of (S)-laudanosine was accomplished by Polonovski-type reaction to give (S)-norlaudanosine. Condensation of (S)-norlaudanosine with homoveratric acid, and subsequent Bischler-Napieralski cyclization, LiAlH₄ reduction, and O-demethylation furnished (8R,14S)-(?)-javaberine A, corresponding to antipode of natural javaberine A. (8S,14S)-(?)-Javaberine A, which corresponds to C14-epimer of natural javaberine A, was also successfully synthesized.

Full text of DOI:10.1016/j.tet.2021.132165

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric total synthesis of (ꢀ)-javaberine A and (ꢀ)-epi-javaberine
A based on catalytic intramolecular hydroamination of N-methyl-2-(2-
styrylaryl)ethylamine
Saho Uenishi a, Rina Kakigi a, Kumiko Hideshima a, Akari Miyawaki a, Junpei Matsuoka a,
,
*
Tokutaro Ogata b, Kiyoshi Tomioka a, Yasutomo Yamamoto a
a Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Japan
b Faculty of Pharmaceutical Sciences, Hokuriku University, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric total synthesis of (ꢀ)-javaberine A and its epimer was achieved by utilizing two methods for
isoquinoline synthesis, asymmetric hydroamination of N-methyl-2-(2-styrylaryl)ethylamine and
Bischler-Napieralski cyclization. Intramolecular asymmetric hydroamination of N-methyl aminoalkene 4
was catalyzed by lithium amideechiral bisoxazoline to give tetrahydroisoquinoline (S)-laudanosine with
good enantioselectivity in excellent yield. N-Demethylation of (S)-laudanosine was accomplished by
Polonovski-type reaction to give (S)-norlaudanosine. Condensation of (S)-norlaudanosine with homo-
veratric acid, and subsequent Bischler-Napieralski cyclization, LiAlH4 reduction, and O-demethylation
furnished (8R,14S)-(ꢀ)-javaberine A, corresponding to antipode of natural javaberine A. (8S,14S)-
(ꢀ)-Javaberine A, which corresponds to C14-epimer of natural javaberine A, was also successfully
synthesized.
Received 1 March 2021
Received in revised form
9 April 2021
Accepted 12 April 2021
Available online xxx
Keywords:
Hydroamination
Lithium amide
Cyclization
© 2021 Elsevier Ltd. All rights reserved.
Heterocycles
Berberine alkaloid
1. Introduction
highly useful for the asymmetric synthesis of benzyltetrahy-
droisoquinoline (S)-laudanosine (5) (Scheme 1) [8].
Berberines are a class of isoquinoline alkaloids with a wide
range of biological activities [1]. Berberines with C8-substituents
have attracted increased attention due to their interesting bio-
logical properties [2]; for example, javaberine A (1) inhibits
The corresponding N-demethylated product, norlaudanosine
(6), is a key intermediate for the synthesis of C8-substituted tet-
rahydroprotoberberines [9]. Herein, we report the asymmetric
total synthesis of (ꢀ)-javaberine A ((ꢀ)-1) and its epimer based on
two isoquinoline synthesis methods; our asymmetric intra-
molecular hydroamination and Bischler-Napieralski cyclization
(Scheme 1).
lipopolysaccharide-induced tumor necrosis factor-
a and nitric
oxide production [3], and O-methylcorytenchirine (2) [4] and
coralydine (3) [5] exhibit inhibitory activity against human cyto-
chrome P450 [6] (Fig. 1). We investigated lithium amide-catalyzed
hydroamination of aminoalkenes [7], and found this method to be
* Corresponding author.
E-mail address: yayamamo@dwc.doshisha.ac.jp (Y. Yamamoto).
Fig. 1. C8-substituted tetrahydroprotoberberine alkaloids.
https://doi.org/10.1016/j.tet.2021.132165
0040-4020/© 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: S. Uenishi, R. Kakigi, K. Hideshima et al., Asymmetric total synthesis of (ꢀ)-javaberine A and (ꢀ)-epi-javaberine A based
on catalytic intramolecular hydroamination of N-methyl-2-(2-styrylaryl)ethylamine, Tetrahedron, https://doi.org/10.1016/j.tet.2021.132165

S. Uenishi, R. Kakigi, K. Hideshima et al.
Tetrahedron xxx (xxxx) xxx
Scheme 1. Synthetic strategy for (ꢀ)-javaberine A by asymmetric hydroamination and
Bischler-Napieralski cyclization.
2. Results and discussion
Scheme 3. Preparation of cyclization precursor 4.
We previously reported that norlaudanosine (6) is a useful in-
termediate for the racemic total synthesis of javaberine A (1) [9a],
O-methylcorytenchirine (2) [9c], coralydine (3) [9c], and related
C8-substituted tetrahydroprotoberberines [9b]. The most straight-
forward approach to synthesizing optically active norlaudanosine
(6) [10] is asymmetric hydroamination of primary amine 7; how-
ever, according to the Kouklovsky report, this reaction is not ster-
eoselective, affording racemic norlaudanosine (6) in 51% yield
(Scheme 2) [11]. Therefore, we planned a catalytic asymmetric
hydroamination of N-methyl secondary amine 4 followed by N-
demethylation to obtain optically active norlaudanosine (6) [8].
The cyclization precursor of secondary amine 4 was synthesized
as we previously reported (Scheme 3) [8]. Heck reaction of 2-
obtained with 76% ee at ꢀ30 ꢁC using chiral ligand L2 (entry 5) [8].
Unfortunately, conducting the reaction at ꢀ40 ꢁC resulted in both
poor yield and poor enantioselectivity because 5 was sparingly
soluble in toluene at ꢀ40 ꢁC (entry 6). Recrystallization in hexane/
AcOEt resulted in optically pure (S)-laudanosine (5) in 64% yield
from the 76% ee of 5 obtained in entry 5.
The next task was N-demethylation of laudanosine (5) to yield
norlaudanosine (6), which is the synthetic intermediate of the
racemic total synthesis of javaberine A (1) and its epimer [9a]. For
N-demethylation of 5, we first investigated an N-acyla-
tionedemethylationedeacylation strategy [12]. Treatment of 5
with 1-chloroethyl chloroformate in dichloroethane followed by
bromo-4,5-dimethoxybenzaldehyde
(8)
with
3,4-
dimethoxystyrene (9) gave stilbene 10 in 89% yield. Applying the
Henry reaction to 10 followed by LiAlH4 reduction afforded primary
amine 7. Finally, formylation of 7 followed by LiAlH4 reduction
furnished N-methyl secondary amine 4.
Table 1
Catalytic asymmetric hydroamination of N-methyl aminoalkene 4.
We first screened chiral bisoxazoline (Box) ligand catalysts L1-
L4 for lithium amide-catalyzed asymmetric hydroamination of N-
methyl aminoalkene 4. A solution of aminoalkane 4 and chiral Box
L1 (R ¼ i-Pr, 0.5 equiv) in toluene was treated with n-BuLi (0.3
equiv) and i-Pr2NH (0.4 equiv) at 0 ꢁC for 5 h to give (S)-laudanosine
(5) with 43% ee in 99% yield (Table 1, entry 1). We also examined
another Box ligand, L2-L4, and found that leucine-derived bisox-
azoline L2 afforded 5 with moderate enantioselectivity (62%) (en-
tries 2e4). We then evaluated the reaction temperature, and 5 was
entry
ligand
temp
time
yield
ee
R/S
1a
2
3
L1
L2
L3
L4
L2
L2
0
0
0
0
ꢁC
ꢁC
ꢁC
ꢁC
5 h
5 h
5 h
5 h
26 h
24 h
99%
98%
99%
99%
96%
10%
43%
62%
45%
35%
76%
9%
S
S
S
R
S
S
4
5b, c
6
ꢀ30 ꢁC
ꢀ40 ꢁC
a
With 0.4 equiv of i-Pr2NH. b With 0.45 equiv of n-BuLi. c Quoted from ref. 8.
Scheme 2. Hydroamination of primary amine 7 in the presence of chiral Box L2 re-
ported by Kouklovsky's group.
2

S. Uenishi, R. Kakigi, K. Hideshima et al.
Tetrahedron xxx (xxxx) xxx
Scheme 4. Unsuccessful N-demethylation by N-acylation.
Scheme 5. Polonovski-type N-demethylation of (S)-5.
methanol, however, did not afford the desired norlaudanosine (6),
and aminoalkene 4 (E/Z 19/1) was quantitatively obtained (Scheme
4). This result can be explained as follows: N-acylammonium 13,
generated from laudanosine (5) with 1-chloroethyl chloroformate,
underwent
b-elimination to give 14, whose deacylation yielded
aminoalkene 4.
Scheme 6. Asymmetric total synthesis of (ꢀ)-javaberine A and its epimer.
Next, we evaluated a Polonovski-type N-demethylation [13].
Oxidation of (S)-laudanosine (5) with mCPBA gave the corre-
sponding N-oxide 15 as a mixture of diastereomers, and subsequent
acidification and treatment with hydrated ferrous sulfate afforded
(S)-norlaudanosine (6) in 47% overall yield (Scheme 5). Specific
rotation of (S)-6 revealed that the optical purity was maintained
during the N-demethylation (see experimental section), and
therefore optically pure (S)-norlaudanosine (6) was now available
based on our asymmetric hydroamination.
Asymmetric total synthesis of javaberine A (1) and its epimer
was achieved from (S)-norlaudanosine (6) using the procedure for
racemic synthesis of javaberine A (Scheme 6) [9a]. Thus, conden-
sation of (S)-norlaudanosine (6) with homoveratric acid (16) gave
amide 17 in 84% yield. Bischler-Napieralski cyclization of 17 fol-
lowed by LiAlH4 reduction afforded javaberine A hexamethylate
(19, 23%) and epi-javaberine A hexamethylate (epi-19, 74%), and
these diastereomers were easily separated by column chromatog-
raphy [14,15]. We treated each of 19 and epi-19 with BBr3 to give
(ꢀ)-javaberine A ((ꢀ)-1) and epi-javaberine A (epi-1) as a hydro-
bromide salt, and subsequent acetylation by Ac2O-pyridine led to
(ꢀ)-javaberine A hexaacetate (20) and its epimer (epi-20) [16]. The
absolute configuration of natural javaberine A (1) was previously
established as (8S,14R) on the basis of its optical rotation (hex-
20
rotation of our synthetic 20 was [
a
]
ꢀ 73.3 (c 1.04, CHCl3). As
D
Hiemstra described, the reason for the remarkable differences in
the magnitudes of the rotation values between synthetic and nat-
ural 20 is unclear [17]. We also performed chiral HPLC analysis of 19
and 20 and confirmed that these compounds were not racemized
during the synthesis. The absolute configuration of epi-19 and epi-
20 should be (8S, 14S), and therefore we also achieved the asym-
metric total synthesis of C14-epimer of natural javaberine A (epi-1).
3. Conclusion
Asymmetric total synthesis of (ꢀ)-javaberine A and its epimer
was achieved by utilizing two methods for isoquinoline synthesis,
asymmetric hydroamination and Bischler-Napieralski cyclization.
Intramolecular asymmetric hydroamination of N-methyl secondary
amine 4 proceeded smoothly to give (S)-laudanosine (5) with good
enantioselectivity, and subsequent recrystallization afforded opti-
cally pure (S)-5. N-Demethylation of (S)-laudanosine (5) was ach-
ieved by the Polonovski-type reaction without loss of optical purity
to yield (S)-norlaudanosine (6). (ꢀ)-Javaberine A and its epimer
were synthesized from (S)-6 using our previously established
procedure. Because norlaudanosine (6) is a key intermediate of C8-
substituted tetrahydroprotoberberines, the present method opens
the door for the asymmetric synthesis of C8-substituted
tetrahydroprotoberberines.
aacetate (þ)-20 from natural javaberine A: [
a
]
24 þ5.0 (c 0.9, CHCl3)
D
20
[3], Hiemstra's synthetic (þ)-20, [
a
]
þ112.5 (c 0.40, CHCl3) [17]).
D
Starting from (S)-6, the absolute configuration of our synthesized
javaberine A hexaacetate (20) should be (8R,14S), which corre-
sponds to the antipode of natural javaberine A. Indeed, the specific
3

S. Uenishi, R. Kakigi, K. Hideshima et al.
Tetrahedron xxx (xxxx) xxx
4. Experimental section
under ice-water bath. After stirring at rt for 6 h, the excess of LiAlH4
was successively quenched with water (5.3 mL), 10% NaOH (5.3 mL)
and water (15.9 mL). After filtration, the filtrate was dried over
K2CO3. Concentration and column chromatography (AcOEt, then
CHCl3/EtOH/25% aq. NH3 160/9/1) gave 7 (4.11 g, 86%) as a right
brown oil. 1H NMR: 1.25 (2H, br s), 2.88 (2H, t, J ¼ 6.7), 2.95 (2H, t,
J ¼ 6.7), 3.89, 3.90, 3.938, and 3.943 (each 3H, s), 6.70 (1H, s), 6.85
(1H, d, J ¼ 15.9), 6.87 (1H, d, J ¼ 8.3), 7.03e7.09 (2H, m), 7.11 (1H, s),
7.17 (1H, d, J ¼ 15.9). 13C NMR: 37.0 (CH2), 43.4 (CH2), 55.84 (CH3),
55.87 (CH3), 55.88 (CH3), 55.92 (CH3), 108.6 (CH), 109.3 (CH), 111.3
(CH), 113.1 (CH), 119.2 (CH), 124.2 (CH), 128.3 (CH), 128.8 (C), 130.2
(C), 130.9 (C), 147.7 (C), 148.5 (C), 148.8 (C), 149.1 (C). IR: 3368, 3306,
1605, 1516. EIMS m/z: 343 (Mþ). Anal. Calcd for C20H25NO4: C,
69.95; H, 7.34; N, 4.08. Found: C, 69.80; H, 7.44; N, 4.02.
All melting points are uncorrected. 1H NMR (500 MHz) and 13
C
NMR (125 MHz) were measured in CDCl3 unless otherwise
mentioned. Chemical shift values were expressed in ppm relative to
an internal reference of tetramethylsilane (0 ppm) in 1H NMR and
CDCl3 (77.0 ppm) in 13C NMR. 13C peak multiplicity assignments
were made based on DEPT data. Coupling constants were shown in
Hertz. Abbreviations are as follows: s, singlet; d, doublet; t, triplet;
m, multiplet; br, broad. IR spectroscopy of oil and solid samples
were measured as neat liquid films and KBr pellets, respectively.
The wave-numbers of maximum absorption peaks of IR spectros-
copy were presented in cmꢀ1. Column chromatography was per-
formed using silica gel or amino-silica gel (amino-SiO2, purchased
from Yamazene Corporation) as a stationary phase.
4.4. (E)-N-(2-(3,4-Dimethoxystyryl)-4,5-dimethoxyphenyl)
4.1. (E)-2-(3,4-Dimethoxystyryl)-4,5-dimethoxybenzaldehyde (10)
formamide (12) [8]
[8]
A mixture of 7 (31 g, 90 mmol), HCO2H (100 mL, 2.7 mol) and
Ac2O (86 mL, 0.9 mol) was stirred at rt for 2 h. The mixture was
diluted with water, basified with 10% NaOH and extracted with
CHCl3. The organic extracts were washed with brine and dried over
Na2SO4. Concentration and column chromatography (AcOEt/CHCl3
1/1, then CHCl3/EtOH/25% aq. NH3 80/9/1) followed by recrystalli-
zation from AcOEt/hexane gave 12 (29.4 g, 88%) as colorless needles
of mp 131.5e132.5 ꢁC. 1H NMR: 2.98 and 3.52 (each 2H, t, J ¼ 7.1),
3.90, 3.91, 3.95, and 3.99 (each 3H, s), 5.64 (1H, br s), 6.68 (1H, s),
6.87 (1H, d, J ¼ 15.9), 6.88 (1H, d, J ¼ 8.3), 7.09 (1H, dd, J ¼ 1.6, 8.3),
Under argon atmosphere, to a suspension of K3PO4 (50 g,
236 mmol), 8 (41.3 g, 169 mmol) and 9 (111 g, 674 mmol) in N,N-
dimethylacetamide (339 mL) was added Pd(OAc)2 (3.79 g,
16.9 mmol). The mixture was heated at 140 ꢁC for 0.5 h. Additional
Pd(OAc)2 (1.26 g, 5.63 mmol) was added and the mixture was
stirred for 0.5 h at the same temperature. The mixture was poured
onto ice water, filtered through Celite and extracted with CHCl3. The
organic extracts were washed with water and brine, and dried over
Na2SO4. Concentration and column chromatography (SiO2, AcOEt/
hexane 10/1, then AcOEt) followed by recrystallization from AcOEt/
hexane gave 10 (49 g, 89%) as yellow needles of mp 158e159 ꢁC. 1H
NMR: 3.92, 3.96, 3.97, and 4.03 (each 3H, s), 6.89 (1H, d, J ¼ 8.3),
6.91 (1H, d, J ¼ 15.9), 7.09e7.11 (3H, m), 7.38 (1H, s), 7.75 (1H, d,
J ¼ 15.9), 10.33 (1H, s). 13C NMR: 55.69 (CH3), 55.74 (CH3), 55.8
(CH3), 55.9 (CH3), 108.5 (CH), 108.9 (CH), 111.0 (CH), 111.1 (CH), 120.1
(CH), 121.4 (CH), 126.2 (C), 129.8 (C), 132.9 (CH), 135.8 (C), 148.5 (C),
149.1 (C), 149.3 (C), 153.6 (C), 190.0 (CH). IR (KBr): 1663, 1597, 1512.
EIMS m/z: 328 (Mþ). Anal. Calcd for C19H20O5: C, 69.50; H, 6.14.
Found: C, 69.69; H, 6.08.
7.14 (1H, s), 7.16 (1H, d, J ¼ 1.6), 7.27 (1H, d, J ¼ 15.9), 8.16 (1H, s). 13
C
NMR: 32.7 (CH2), 39.6 (CH2), 55.93 (CH3), 55.97 (CH3), 55.99 (CH3),
56.00 (CH3), 108.5 (CH), 109.0 (CH), 111.3 (CH), 113.0 (CH), 119.8
(CH), 123.6 (CH), 128.8 (CH), 128.9 (C), 129.2 (C), 130.7 (C), 148.1 (C),
148.7 (C), 149.0 (C), 149.3 (C), 161.3 (CH). IR: 3364, 1674, 1605, 1516.
EIMS m/z: 371 (Mþ). Anal. Calcd for C21H25NO5: C, 67.91; H, 6.78; N,
3.77. Found: C, 67.69; H, 6.81; N, 3.73.
4.5. (E)-2-(2-(3,4-Dimethoxystyryl)-4,5-dimethoxyphenyl)-N-
methylethanamine (4) [8,19]
4.2. 4-(4,5-Dimethoxy-2-((E)-2-nitrovinyl)styryl)-1,2-
dimethoxybenzene (11) [8,18]
To a 1.0 M THF solution of LiAlH4 (17.8 mL,17.8 mmol) was added
12 (1.65 g, 4.46 mmol) in dry THF (80 mL) under ice-water bath. The
mixture was stirred for 48 h at rt and then quenched with water
(0.7 mL), 10% NaOH (0.7 mL) and water (2.1 mL) at 0 ꢁC. After
filtration, the filtrate was dried over K2CO3 and concentrated. Col-
umn chromatography (AcOEt/CHCl3 1/1, then CHCl3/ethanol/25%
aq. NH3 80/9/1) followed by recrystallization from AcOEt/hexane
gave 4 (1.47 g, 92%) as colorless needles of mp 108e109 ꢁC. 1H NMR:
1.51 (1H, br s), 2.46 (3H, s), 2.82 (2H, t, J ¼ 7.1), 2.93 (2H, t, J ¼ 7.1),
3.90, 3.91, 3.94, and 3.95 (each 3H, s), 6.72 (1H, s), 6.86 (1H, d,
J ¼ 15.9), 6.87 (1H, d, J ¼ 8.2), 7.05 (1H, d, J ¼ 1.8), 7.08 (1H, dd,
J ¼ 1.8, 8.2), 7.11 (1H, s), 7.20 (1H, d, J ¼ 15.9). 13C NMR: 33.3, 36.3,
53.0, 55.80, 55.82, 55.85, 108.5, 109.1, 111.3, 113.0, 119.3, 124.0, 128.2,
128.6, 130.3, 130.9, 147.6, 148.5, 148.7, 149.1. IR: 3317, 1605, 1516.
EIMS m/z: 357 (Mþ).
A solution of 10 (656 mg, 2 mmol) and NH4OAc (154 mg,
2 mmol) in dry nitromethane (3.8 mL) was stirred at 100 ꢁC for 2 h
and then concentrated. The residue was partitioned between AcOEt
and water. The aqueous layer was extracted with AcOEt, and the
combined organic extracts were washed with water and brine, and
dried over Na2SO4. Concentration and column chromatography
(AcOEt/hexane 2/1) followed by recrystallization from AcOEt/hex-
ane gave 11 (712 mg, 96%) as red needles of mp 180e181 ꢁC. 1H
NMR: 3.93, 3.95, 3.97, and 4.00 (each 3H, s), 6.86 (1H, d, J ¼ 15.9),
6.90 (1H, d, J ¼ 8.3), 6.96 (1H, s), 7.07 (1H, d, J ¼ 2.2), 7.08 (1H, s), 7.11
(1H, dd, J ¼ 2.2, 8.3), 7.24 (1H, d, J ¼ 15.9), 7.51 (1H, d, J ¼ 13.2), 8.45
(1H, d, J ¼ 13.2). 13C NMR: 55.90 (CH3), 55.91 (CH3), 56.0 (CH3 x 2),
109.1 (CH), 109.2 (CH), 109.4 (CH), 111.3 (CH), 120.2 (CH), 120.3 (C),
122.3 (CH), 129.8 (C), 133.1 (CH), 134.5 (C), 136.0 (CH), 136.7 (CH),
148.9 (C), 149.3 (C), 149.6 (C), 152.7 (C). IR: 3109, 1620, 1597, 1516.
EIMS m/z: 371 (Mþ). Anal. Calcd for C20H21NO6: C, 64.68; H, 5.70; N,
3.77. Found: C, 64.47; H, 5.78; N, 3.60.
4.6. General procedure for asymmetric hydroamination of 4
(Table 1, entry 2)
Under argon atmosphere, to a solution of L2 (147 mg, 0.5 mmol)
4 (358 mg, 1.0 mmol) in toluene (20 mL) was added i-Pr2NH
(0.04 mL, 0.3 mmol) and n-BuLi (1.6 N in hexane, 0.19 mL, 0.3 mmol)
at 0 ꢁC, and the solution was stirred for 5 h. The reaction mixture
was quenched with satd. NH4Cl (5 mL) and basified with 10%
aqueous K2CO3. The whole was extracted with AcOEt. The organic
extracts were washed with brine and dried over K2CO3.
4.3. (E)-2-(2-(3,4-Dimethoxystyryl)-4,5-dimethoxyphenyl)
ethanamine (7) [8]
To a suspension of LiAlH4 (5.28 g,139 mmol) in dry THF (150 mL)
was added a solution of 11 (12.9 g, 34.8 mmol) in dry Et2O (550 mL)
4

S. Uenishi, R. Kakigi, K. Hideshima et al.
Tetrahedron xxx (xxxx) xxx
Concentration and column chromatography (hexane/AcOEt 1/1 to
0/1) gave 5 (350 mg, 98%) as a pale yellow solid. 62% ee (HPLC,
Daicel Chiralcel OD-H, hexane/i-PrOH 7/3, 1.0 mL/min, 254 nm,
major 7.2 min and minor 17.9 min).
concentrated to give crude N-oxide 15 as brown oil. HCleMeOH
(2 mL) was added to crude 15 and the mixture was concentrated
to give landanosine N-oxideꢂHCl as a pale yellow solid (156 mg).
Laudanosine N-oxideꢂHCl was then dissolved in MeOH (7.5 mL)
followed by the addition of FeSO4ꢂ7H2O (180 mg, 0.65 mmol) at
0 ꢁC. The reaction mixture was stirred at room temperature for 1 h.
The solvent was removed in vacuo and the residue redissolved in a
0.1 M EDTA aq. NH3 (20 mL). The aqueous phase was then extracted
with CHCl3 (30 mL x 3). The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated. Column chro-
matography (amino-SiO2, hexane/AcOEt 3/7 to 1/4) gave 6 as pale a
yellow oil (32.0 mg, 47%).
4.7. (S)-(þ)-Laudanosine (5)(Table 1, entry 5) [8,20]
Under argon atmosphere, to a solution of L2 (147 mg, 0.5 mmol)
and i-Pr2NH (0.04 mL) in toluene (5 mL) was added n-BuLi (1.6 N in
hexane, 0.09 mL, 0.15 mmol) at ꢀ78 ꢁC, and the solution was stirred
for 10 min. A solution of 4 (179 mg, 0.5 mmol) in toluene (10 mL)
was added over 2.5 h by a syringe pump at ꢀ30 ꢁC. After addition of
n-BuLi (1.6 N in hexane, 0.09 mL, 0.15 mmol), another solution of 4
(179 mg, 0.5 mmol) in toluene (10 mL) was added over 2.5 h.
Additional n-BuLi (1.6 N in hexane, 0.09 mL, 0.15 mmol) was added
and then the solution was stirred for 21 h at the same temperature
[21]. The reaction mixture was quenched with satd. NH4Cl (5 mL)
and basified with 10% aqueous K2CO3. The whole was extracted
with AcOEt. The organic extracts were washed with brine and dried
over K2CO3. Concentration and column chromatography (hexane/
AcOEt 1/1 to 0/1) gave 5 (344 mg, 96%) as a pale yellow solid of mp
4.10. Laudanosine-N-oxide (15)
An analytical sample of N-oxide 15 was obtained as follows.
Crude N-oxide 15 was partitioned in CH2Cl2 (5 mL) and satd
NaHCO3 aq. (5 mL), and separated aqueous phase was extracted
with CH2Cl2 (5 mL x 3). Combined organic layers were washed with
brine, dried over Na2SO4, and concentrated to give 15. 1H NMR (dr
6/4): 2.47 (t, 0.4H, J ¼ 11.5, 12.0), 2.82 (dd, 0.6H J ¼ 10.0, 13.5), 2.98
(ddd, 0.6H J ¼ 17.2, 6.9, 6.9), 3.07e3.20 (m, 0.8H), 3.24 (s, 3H), 3.32
(ddd, 0.6H J ¼ 17.2, 6.3, 6.3), 3.42 (s, 1.2H), 3.50 (m, 0.4H), 3.54 (s,
1.8H), 3.61e3.73 (m, 1.2H), 3.79 (m, 0.4H), 3.820 (s, 1,8H), 3.824 (s,
1.2H), 3.84 (s, 3H), 3.86 (s, 1.2H), 3.87 (s, 1.8H), 4.07 (dd, 0.6H,
J ¼ 13.5, 1.8), 4.12 (m, 0.4H), 4.48 (dd, 0.4H, J ¼ 12.0, 2.3), 4.63 (dd,
0.6H, J ¼ 10.0, 1.8), 5.59 (s, 0.4H), 6.39 (s, 0.6H), 6.49 (dd, 0.4H,
J ¼ 8.0, 1.7), 6.60e6.65 (m, 1H), 6.72e6.84 (m, 2.6H). 13C NMR: 26.1.
(CH2), 26.8 (CH2), 37.4 (CH2), 38.4 (CH2), 52.8 (CH3), 55.3 (CH3), 55.6
(CH3), 55.81 (CH3), 55.83 (CH3), 55.89 (CH3), 55.94 (CH3), 56.2
(CH3), 59.7 (CH3), 63.5 (CH2), 78.5 (CH), 79.0 (CH), 110.4. (CH),
110.68 (CH), 110.74 (CH), 110.88 (CH), 110.91 (CH), 111.2. (CH), 111.9
(CH), 113.1 (CH), 119.8 (C), 121.2 (CH), 122.3 (C), 122.8 (CH), 125.78
(C), 125.82 (C), 129.9 (C), 130.1 (C), 146.6 (C), 147.4 (C), 147.7 (C),
147.9 (C), 148.4 (C), 148.7 (C), 148.9 (C), 149.3 (C). IR: 3395, 3019,
2958, 2837, 1519, 1466, 1261. EIMS m/z: 373 (Mþ), 314, 206. HRMS-
ESI m/z: [MþNa]þ calcd for C21H27N1NaO5, 396.1787; found,
396.1787.
88e90 ꢁC. [
a
]
25 þ35.9 (c 1.05, CHCl3). 76% ee (HPLC, Daicel Chiralcel
D
OD-H, hexane/i-PrOH 7/3, 1.0 mL/min, 254 nm, major 7.2 min and
minor 17.9 min). Recrystallization of 5 (76% ee) from hexane/AcOEt
afforded 5 (220 mg, 64%) of 99% ee as a white solid of mp 85e86 ꢁC.
25
[
[
a
a
]
]
þ57.3 (c 0.98, CHCl3) [20]. (Lit. 20b: mp 87e88 ꢁC and
D
þ54.4 (c 0.20, CHCl3). 1H NMR: 2.54 (3H, s), 2.58 (1H, m),
29
D
2.73e2.86 (3H, m), 3.12e3.20 (2H, m), 3.57 (3H, s), 3.69 (1H, m),
3.79 (3H, s), 3.84 (3H, s), 3.85 (3H, s), 6.07 (1H, s), 6.56 (1H, s), 6.60
(1H, d, J ¼ 1.8), 6.64 (1H, dd, J ¼ 1.8, 8.0), 6.77 (1H, d, J ¼ 8.0). 13
C
NMR: 25.5 (CH2), 40.8 (CH2), 42.6 (CH3), 46.9 (CH2), 55.5 (CH3),
55.68 (CH3), 55.73 (CH3), 55.8 (CH3), 64.8 (CH), 111.0 (CH), 111.1
(CH), 111.2 (CH), 113.0 (CH), 121.8 (CH), 126.1 (C), 129.3 (C), 132.5 (C),
146.3 (C),147.26 (C),147.31 (C),148.6 (C). IR: 2932, 2839, 2793,1605,
1512. EIMS m/z: 357 (Mþ).
4.8. Unsuccessful N-demethylation of 5 by N-acylation (Scheme 4)
To a solution of 5 (107 mg, 0.3 mmol) in 1,2-dichloroethane
(1.5 mL) was added dropwise 1-chloroethyl chloroformate
(0.08 mL, 0.72 mmol) at 0 ꢁC under argon. The mixture was stirred
for 15 min at 0 ꢁC and then refluxed for 24 h. The mixture was
cooled to room temperature and concentrated under reduced
pressure. To this mixture was added 1.2 mL of MeOH, and the re-
action was refluxed 24 h. After cooling, the solvent was evaporated
under reduced pressure. To the mixture were added satd NaHCO3
(10 mL) and AcOEt (10 mL), and the separated aqueous layer was
extracted with AcOEt (10 mL x 2). The combined organic layers
were washed with brine, dried over Na2SO4, filtered and concen-
trated to afford pale yellow solids (103 mg). The residue was pu-
rified by column chromatography (SiO2, CHCl3/AcOEt 1/1) to give 4
(109 mg, quant, E/Z 19/1) as pale brown solid. 1H NMR of (E)-4: 1.65
(1H, br s), 2.46 (3H, s), 2.82 (2H, t, J ¼ 7.1), 2.93 (2H, t, J ¼ 7.1), 3.90
(3H, s), 3.91 (3H, s), 3.94 (3H, s), 3.95 (3H, s), 6.72 (1H, s), 6.86 (1H, d,
J ¼ 15.9), 6.87 (1H, d, J ¼ 8.2), 7.05 (1H, d, J ¼ 1.8), 7.08 (1H, dd,
J ¼ 1.8, 8.2), 7.11 (1H, s), 7.20 (1H, d, J ¼ 15.9). (Z)-4: 1.65 (1H, br s),
2.39 (3H, s), 2.75 (4H, m), 3.56 (3H, s), 3.64 (3H, s), 3.82 (3H, s), 3.87
(3H, s), 6.49 (1H, d, J ¼ 12.0), 6.58 (1H, d, J ¼ 12.0), 6.64e7.20 (9H,
m).
4.11. (S)-Norlaudanosine (6) [10,22]
1H NMR: 2.65e2.78 (2H, m), 2.82e2.92 (2H, m), 3.14e3.22 (2H,
m), 3.83 (3H, s), 3.847 (3H, s), 3.851 (3H, s), 3.86 (3H, s), 4.12 (1H, dd,
J ¼ 4.3, 9.4), 6.59 (1H, s), 6.66 (1H, s), 6.74 (1H, d, J ¼ 1.8), 6.79 (1H,
dd, J ¼ 1.8, 8.0), 6.82 (1H, d, J ¼ 8.0). [
a
]
25 ꢀ 24.8 (c 0.29, CHCl3). Lit.
D
25
[
a
]
ꢀ 23.6 (c 0.85, CHCl3) [10].
D
4.12. (S)-1-(1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-3,4-
dihydroisoquinolin-2(1H)-yl)-2-(3,4-dimethoxyphenyl)ethan-1-one
(17) [9a]
A mixture of (S)-norlaudanosine 6 (3.4 g, 9.9 mmol), homo-
veratric acid 16 (1.94 g, 9.9 mmol), HOBt (1.49 g, 11.0 mmol), EDC
(2.1 mL, 11.0 mmol) and Et3N (4.1 mL, 29.7 mmol) in CH2Cl2
(100 mL) was stirred at room temperature for 17 h. The mixture was
diluted with CH2Cl2 (100 mL) and was washed with 10% HCl (20 mL
x 2), satd NaHCO3 (20 mL x 2) and brine (20 mL), dried over Na2SO4,
filtrated and evaporated to afford pale brown solids. Purification by
column chromatography (SiO2, AcOEt) gave amide 17 (4.36 g, 84%)
as yellow solids. 1H NMR (the ratio of rotamer is 66/34): 2.53e2.58
(1.32H, m), 2.69 (0.34H, m), 2.92 (0.66H, m), 2.94 (0.66H, dd, J ¼ 8.0,
13.2), 2.98 (0.34H, dd, J ¼ 5.1, 14.0), 3.03 (0.34H, d, J ¼ 16.0), 3.07
(0.34H, dd, J ¼ 9.2, 14.0), 3.11 (0.66H, dd, J ¼ 5.7, 13.7), 3.20 (0.34H,
dt, J ¼ 4.6, 13.0), 3.25 (0.34H, d, J ¼ 16.0), 3.39 (0.66H, m), 3.61
(1.98H, s), 3.68 (1.02H, s), 3.69e3.73 (1.66H, m), 3.75 (1.98H, s), 3.80
4.9. Polonovski-type N-demethylation of 5 (Scheme 5)
To a solution of (S)-laudanosine (5) (71.4 mg, 0.2 mmol) in
CH2Cl2 (2 mL) was added mCPBA (69.0 mg, 0.3 mmol) at 0 ꢁC. The
reaction mixture was stirred at room temperature for 2 h, and then
5

S. Uenishi, R. Kakigi, K. Hideshima et al.
Tetrahedron xxx (xxxx) xxx
(1.98H, s), 3.83e3.84 (6H, m), 3.85 (1.02H, s) 3.86 (3H, s), 3.88
(1.02H, s), 4.83 (0.34H, m), 4.91 (0.34H, dd, J ¼ 5.1, 9.0), 5.67 (0.66H,
dd, J ¼ 5.6,13), 6.18 (0.66H, s), 6.40 (0.34H, s), 6.43e6.45 (0.68H, m),
6.51e6.53 (1.32H, m), 6.72e6.83 (4.66H, m), 6.85 (0.34H, s). 13C
NMR: 27.9 (CH2), 28.3 (CH2), 35.2 (CH2), 39.6 (CH2), 41.1 (CH2), 41.2
(CH2), 41.8 (CH2), 42.4 (CH), 54.0 (CH), 56.6 (CH3), 55.8 (CH3), 55.93
(CH3), 55.96 (CH3), 55.99 (CH3), 56.1 (CH3), 58.6 (CH), 110.1 (CH),
110.82 (CH), 110.89 (CH), 110.93 (CH), 111.2 (CH), 111.4 (CH), 111.5
(CH), 111.6 (CH), 111.8 (CH), 111.9 (CH), 112.8 (CH), 112.9 (CH), 120.8
(CH), 120.9 (CH), 121.9 (CH), 122.1 (CH), 125.6 (C), 126.7 (C), 127.5
(C), 127.7 (C), 128.0 (C), 128.3 (C), 130.5 (C), 130.7 (C), 147.0 (C), 147.4
(C), 147.69 (C), 147.72 (C), 147.9 (C), 148.2 (C), 148.3 (C), 148.9 (C),
145.1 (C), 170.1 (C), 170.4 (C). IR: 1630. HRMS-ESI m/z: [MþNa]þ
calcd for C30H35NNaO7, 544.2311; found, 544.2300.
[MþH]þ. HRMS-FAB m/z: [MþH]þ calcd for C30H36NO6, 506.2543;
found, 506.2558. [
a]
20 ꢀ 118.7 (c 0.92, CHCl3). HPLC (OD-H, hexane/
D
i-PrOH 3/2, 1 mL/min, 254 nm) 99% ee, major 34.7 min and minor
16.5 min.
4.14. (8R,14S)-(ꢀ)-Javaberine A hexaacetate (20) [3]
To the solution of 19 (103 mg, 0.2 mmol) in CH2Cl2 (1 mL) was
added BBr3 (1 M solution in CH2Cl2, 2 mL, 2 mmol) at 0 ꢁC. The
mixture was stirred for 1 h, and then MeOH (5 mL) was added, and
the mixture was concentrated to give crude javaberine A hydro-
bromide as brown oil (170 mg). To the residue were added Ac2O
(1.5 mL, 16 mmol) and pyridine (1.5 mL), and the mixture was
stirred for 24 h at room temperature. Concentration followed by
column chromatography (SiO2, hexane/AcOEt 1/2) gave javaberine
4.13. (8R,14S)-(ꢀ)-Javaberine A hexamethylate (19) and (8S,14S)-
epi-javaberine A hexamethylate (epi-19) [9a]
A acetate (71 mg, 52%) as yellow amorphous solids. [
a
]
25 ꢀ 73.3 (c
D
1.04, CHCl3). (lit. [
a
]
24 þ5.0 (c 0.9, CHCl3) in ref 3, [
a
]
20 þ112.5 (c 0.4,
D
D
CHCl3) in ref 17). 1H NMR: 2.264 (3H, s), 2.269 (3H, s), 2.275 (3H, s),
2.278 (3H, s), 2.29 (3H, s), 2.30 (3H, s), 2.72e2.76 (2H, m), 2.82 (1H,
dd, J ¼ 5.7, 13.7 Hz), 2.85e2.98 (3H, m), 3.06 (1H, m), 3.18 (1H, dd,
J ¼ 7.6, 13.7), 3.94 (1H, dd, J ¼ 5.7, 8.0), 4.40 (1H, dd, J ¼ 5.3, 11.0),
6.65 (1H, s) 6.90 (1H, s), 6.95 (1H, s), 6.97 (1H, s), 7.03 (1H, s), 7.06
(1H, d, J ¼ 8.2), 7.09 (1H, br d, J ¼ 8.2). IR: 1761, 1504, 1368, 1201,
1174. HRMS-ESI m/z: [MþH]þ calcd for C36H36N1O12, 674.2238;
found, 674.2223. HPLC (IA-3, hexane/EtOH 3/1, 1 mL/min, 254 nm),
99% ee, major 13.1 min and minor 10.7 min.
A mixture of amide 17 (0.83 g, 1.6 mmol) and phosphoryl
chloride (0.30 mL, 3.2 mmol) in anhydrous MeCN (2.4 mL) was
refluxed for 2 h at 100 ꢁC under Ar. Concentration gave 18 (1.2 g) as
yellow solids. 1H NMR: 2.95 (1H, m), 3.10 (1H, m), 3.18 (1H, dd,
J ¼ 16.6, 16.6), 3.42 (1H, dd, J ¼ 4.6, 16.6), 3.83, (3H, s), 3.87 (1H, m),
3.873 (3H, s), 3.875 (3H, s), 3.91 (3H, s), 3.93 (3H, s), 4.05 (3H, s),
4.87 (1H, m), 4.91 (1H, d, J ¼ 16.6), 5.26 (1H, d, J ¼ 16.6), 5.31 (1H,
dd, J ¼ 4.0, 16.6), 6.49 (1H, dd, J ¼ 1.7, 8.6), 6.67 (1H, s), 6.75 (1H, d,
J ¼ 8.6), 6.82 (1H, s), 6.98 (1H, s), 7.00 (1H, d, J ¼ 1.7), 7.50 (1H, s). 13
C
NMR (DMSO-d6): 28.1(CH2), 34.5 (CH2), 35.5 (CH2), 50.4 (CH2), 55.5
(CH3), 55.6 (CH3), 55.7 (CH3), 55.9 (CH3), 56.4 (CH3), 56.5 (CH3), 59.4
(CH), 109.9 (CH), 111.0 (CH), 111.3 (CH), 112.28 (CH), 112.32 (CH),
113.7 (CH), 119.4 (C), 119.9 (CH), 125.0 (C), 125.8 (C), 126.7 (C), 135.3
(C),148.1 (C x 2),148.1 (C),148.3 (C),149.1 (C),155.8 (C),175.1 (C). IR:
1608, 1518, 1466, 1372, 1280, 1259. HRMS-ESI m/z: [M ꢀ Cl]þ calcd
for C30H34N1O6, 504.2386; found, 504.2371.
To the suspension of crude iminium 18 (1.2 g) in THF (10 mL)
was added LiAlH4 (1 M in THF, 8 mL, 8 mmol) at ꢀ78 ꢁC. The
mixture was stirred for 1 h at ꢀ78 ꢁC, and quenched with water
(0.6 mL), 10% NaOH (0.6 mL) and water (1.8 mL) and then filtered
through a Celite pad. The filtrate was dried over Na2SO4 and
concentrated. Column chromatography (hexane/AcOEt 1/3) gave
epi-19 (616 mg, 74%) as yellow solids and 19 (191 mg, 23%) as yellow
amorphous solids of mp 75e77 ꢁC.
4.15. (8S,14S)-(ꢀ)-epi-Javaberine A hexaacetate (epi-20)
To the solution of epi-19 (330 mg, 0.65 mmol) in CH2Cl2 (8 mL)
was added BBr3 (1 M solution in CH2Cl2, 6.5 mL, 6.5 mmol) at 0 ꢁC.
The mixture was stirred for 1 h, and then MeOH (5 mL) was added,
and the mixture was concentrated to give epi-javaberine A hydro-
bromide as yellow brown oil (432 mg). To the residue were added
Ac2O (3 mL, 32 mmol) and pyridine (3 mL), and the mixture was
stirred for 24 h at room temperature. Concentration followed by
column chromatography (SiO2, hexane/AcOEt 1/2) gave epi-20
25
(164 mg, 38%) as yellow amorphous solids. [
a]
ꢀ 97.1 (c 1.02,
D
CHCl3). 1H NMR: 2.211 (3H, s), 2.214 (3H, s), 2.265 (3H, s), 2.274 (9H,
s), 2.48 (1H, dd, J ¼ 11.5, 15.5), 2.63e2.71 (2H, m), 2.92e2.98 (2H,
m), 3.09 (1H, m), 3.16 (1H, dd, J ¼ 4.5, 14.3), 3.25 (1H, dd, J ¼ 5.2,
11.5), 3.72 (1H, d, J ¼ 6.4), 4.06 (1H, m), 0.6.78 (1H, s), 6.85e6.89
(3H, m), 6.93e6.94 (2H, m), 6.98 (1H, s). 13C NMR: 20.58 (CH3),
20.62 (CH3), 29.8 (CH), 36.0 (CH), 42.1 (CH), 48.2 (CH), 57.8 (CH),
64.7 (CH), 120.3 (CH), 121.5 (CH). 122.3 (CH), 122.7 (CH), 123.2 (CH),
124.9 (CH), 128.4 (CH), 133.9 (C), 134.8 (C), 135.5 (C), 136.7 (C x 2),
139.9 (C x 2), 140.0 (C), 140.1 (C), 140.3 (C), 141.1 (C), 168.2 (C), 168.3
(C), 168.4 (C), 168.5 (C). IR: 1761, 1505, 1369, 1200, 1173. HRMS-ESI
m/z: [MþH]þ calcd for C36H36N1O12, 674.2238; found, 674.2218.
HPLC (IA-3, hexane/AcOEt 1/1, 1 mL/min, 254 nm), 99% ee, major
4.0 min and minor 3.0 min.
19: 1H NMR: 2.79e3.00 (6H, m), 3.10 (1H, m), 3.27 (1H, dd,
J ¼ 5.7, 13.2), 3.57 (3H, s), 3.77 (3H, s), 3.84 (3H, s), 3.86 (3H, s), 3.87
(3H, s), 3.90 (3H, s), 3.95 (1H, dd, J ¼ 5.7, 7.7), 4.40 (1H, dd, J ¼ 5.2,
11.5), 5.98 (1H, s), 6.59 (1H, s), 6.63 (1H, s), 6.65e6.69 (3H, m), 6.78
(1H, d, J ¼ 8.0). 13C NMR: 29.4 (CH2), 33.6 (CH2), 40.2 (CH2), 46.8
(CH2), 50.8 (CH), 55.4 (CH3), 55.7 (CH3 x 2), 55.79 (CH3), 55.88 (CH3),
55.94 (CH3), 66.6 (CH), 109.2 (CH), 110.8 (CH), 110.9 (CH), 111.0 (CH),
111.5 (CH), 113.2 (CH), 121.9 (CH), 125.2 (C), 126.1 (C), 128.9 (C), 131.2
(C), 132.7 (C), 146.2 (C), 147.2 (C), 147.3 (C), 147.4 (C), 147.5 (C), 148.5
(C). IR: 3002, 2935, 1610, 1515, 1465, 1261. HRMS-ESI m/z: [MþNa]þ
calcd for C30H35NNaO6, 528.2362; found, 528.2363. [
1.04, CHCl3). HPLC (OD-H, hexane/i-PrOH 3/2, 1 mL/min, 254 nm)
99% ee, major 20.8 min and minor 34.3 min.
a
]
25 ꢀ 121.9 (c
D
Declaration of competing interest
epi-19: 1H NMR: 2.47 (1H, dd, J ¼ 10.9, 14.9), 2.63e2.69 (2H, m),
2.96 (1H, dd, J ¼ 2.4, 14.6), 3.06e3.14 (3H, m), 3.39 (1H, m),
3.65e3.67 (4H, m), 3.74 (3H, s), 3.81 (3H, s), 3.86 (3H, s), 3.87 (3H, s)
3.88 (3H, s), 3.99 (1H,s), 6.48 (1H, s), 6.53 (1H, s), 6.58e6.60 (4H, m),
6.73 (1H, s). 13C NMR: 30.1 (CH2), 36.7 (CH2), 42.7 (CH2), 48.8 (CH2),
55.6 (CH3), 55.75 (CH3), 55.77 (CH3), 55.8 (CH3 x 2), 56.0 (CH3), 58.5
(CH), 65.4 (CH), 108.8 (CH), 110.0 (CH), 110.5 (CH), 110.8 (CH), 111.3
(CH), 113.3 (CH), 122.3 (CH), 127.2 (C), 128.5 (C), 129.5 (C), 130.6 (C),
131.4 (C), 147.0 (C x 2), 147.1 (C), 147.2 (C), 147.4 (C), 147.9 (C). IR:
2932, 2834, 2811, 2773, 2741, 1612, 1512, 1261. FABMS m/z: 506
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgment
This research was supported in part by JSPS KAKENHI Grant
Numbers 17K08229.
6

S. Uenishi, R. Kakigi, K. Hideshima et al.
Tetrahedron xxx (xxxx) xxx
D.; Doye, S, Eur. J. Org Chem. (2005) 2689.
Appendix A. Supplementary data
[11] A. Pouihes, P.J. Baltaze, C. Kouklovsky, Synlett (2013) 1805.
[12] (a) D. Ghosh, S.E. Snyder, V.J. Watts, R.B. Mailman, D.E. Nichols, J. Med. Chem.
39 (1996) 549;
(b) R.A. Olofson, D.E. Abbott, J. Org. Chem. 49 (1984) 2795.
[13] (a) K.M. Camley, J.A. Ripper, R.D. Singer, P.J. Scammells, J. Org. Chem. 68 (2003)
9847;
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132165.
References
(b) G.B. Kok, P.J. Scammells, Synthesis 44 (2012) 2587.
[14] The Relative Configuration of 19 and Epi-19 Was Determined by NOE Ex-
periments. See Ref. 9a.
[1] (a) M.A. Matulenko, A.I. Meyers, J. Org. Chem. 61 (1996) 573;
(b) S. Gadhiya, S. Madapa, T. Kurtzman, I.L. Alberts, S. Ramsey, N.-K. Pillarsetty,
T. Kalidindi, W.W. Harding, Bioorg. Med. Chem. 24 (2016) 2060.
[2] (a) L.-P. Du, K.-C. Tsai, M.-Y. Li, Q.-D. You, L. Xia, Bioorg. Med. Chem. Lett 14
(2004) 4771;
(b) D.K. Semwal, R.B. Semwal, R. Semwal, Pharmacologia 3 (2012) 539.
[3] H. Shimoda, N. Nishida, K. Ninomiya, H. Matsuda, M. Yoshikawa, Heterocycles
55 (2001) 2043.
[15] In our previous report, the ratio of 19/epi-19 in LiAlH4 reduction of iminium
18 was 9/90. The experimental procedure was slightly different; 18 was
added to the suspension of LiAlH4 in THF in the previous method (ref. 9a),
whereas LiAlH4 solution in THF was added to the suspension of 18 in THF (this
study). Although the reason of the difference in diastereoselectivity Is unclear,
the present procedure provides the desired diastereomer 19 in better yield.
[16] We did not isolate javaberine A (1) and its epimer (epi-1) in this paper
because these compounds were unstable and easily oxidized by air oxygen
(see ref. 17). we and other groups previously reported the isolation of these
compounds (refs. 9a and 17).
[17] J. Kayhan, M.J. Wanner, S. Ingemann, J.H. van Maarseveen, H. Hiemstra, Eur. J.
Org Chem. (2016) 3705.
[18] A. Poschalko, S. Welzig, M. Treu, S. Nerdinger, K. Mereiter, U. Jordis, Tetra-
hedron 58 (2002) 1513.
[19] J.B. Bremner, L.V. Thuc, Aust. J. Chem. 33 (1980) 379.
[20] (a) G.M. Coppola, J. Heterocycl. Chem. 28 (1991) 1769;
(b) S. Kanokmedhakul, K. Kanokmedhakul, R. Lekphrom, J. Nat. Prod. 70
(2007) 1536.
[4] (a) S. Lu, T. Su, T. Kametani, A. Ujiie, M. Ihara, K. Fukumoto, Heterocycles 3
(1975) 459;
(b) S. Lu, T. Su, T. Kametani, A. Ujiie, M. Ihara, K. Fukumoto, J. Chem. Soc.,
Perkin Trans. 1 (1976), 4, 63.
[5] H. Bruderer, J. Metzger, A. Brossi, J. Daly, J. Helv. Chim. Acta 59 (1976) 2793.
[6] K.A. Salminen, A.L. Meyer, A. Jerabkova, L.E. Korhonen, M. Rahnasto,
R.O. Juvonen, P. Imming, H. Raunio, Phytomedicine 18 (2011) 533.
[7] T. Ogata, A. Ujihara, S. Tsuchida, T. Shimizu, A. Kaneshige, K. Tomioka, Tetra-
hedron Lett. 48 (2007) 6648.
[8] T. Ogata, T. Kimachi, K. Yamada, Y. Yamamoto, K. Tomioka, Heterocycles 86
(2012) 469.
[9] (a) Y. Yamamoto, Y. Tabuchi, A. Baba, K. Hideshima, M. Nakano, A. Miyawaki,
K. Tomioka, Heterocycles 88 (2014) 1311;
[21] Due to poor solubility in toluene, 4 was added portionwise to avoid its pre-
cipitation. Portionwise addition of n-BuLi was also required for complete
consumption of 4, indicating that reactive anionic species were gradually
protonated during the reaction.
(b) R. Kakigi, M. Nakano, A. Ueno, A. Miyawaki, K. Tomioka, Y. Yamamoto,
Heterocycles 101 (2020) 512.(c) Kirii, M.; Matsuoka, J.; Miyawaki, A.; Tomioka,
K.; Yamamoto, Y. Heterocycles, in press. doi: 10.3987/COM-20-S(K)49.
[10] Another approach for the asymmetric synthesis of norlaudanosine is asym-
metric hydrogenation of the corresponding dihydroisoquinoline. Mujahidin,
[22] R. Pedrosa, C. Andres, J.M. Iglesias, J. Org. Chem. 66 (2001) 243.
7