The cinchona alkaloid squaramide catalyzed asymmetric Pictet-Spengler reaction and related theoretical studies

Article abstract of DOI:10.1039/c7ob02606d

The asymmetric Pictet-Spengler reaction between tryptamine derivatives and aldehydes has been developed with a cinchona alkaloid squaramide as the catalyst, affording the corresponding tetrahedron-β-carbolines in good to excellent yields and ee values. A rational mechanistic pathway has also been proposed based on DFT calculations.

Full text of DOI:10.1039/c7ob02606d

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Cinchona Alkaloid Squaramide Catalyzed Asymmetric Pictet-
Spengler Reaction and Related Theoretical Studies
Received 00th January 20xx,
Accepted 00th January 20xx
Liang Qi, Huacui Hou, Fei Ling and Weihui Zhong*
The asymmetric Pictet-Spengler reaction between tryptamine derivatives and aldehydes has been developed with
DOI: 10.1039/x0xx00000x
cinchona alkaloid squaramide as the catalyst, affording the corresponding tetrahedron-β-carbolines in good to excellent
www.rsc.org/
yields and ee values.
A rational mechanistic pathway has also been proposed based on DFT calculations.
Introduction
The Pictet-Spengler reaction[1] is an important transformation
in organic synthesis commonly catalyzed by an acid. Starting
from carbonyl compounds and various amines such as phenyl
ethylamines or tryptamines[2], it affords a facile approach to
tetrahedro-β-carbolines or tetrahydroisoquinolines, which
represent important structural motifs in a diverse array of
biologically active natural and unnatural products.[3] Despite
the well-known valuable diasteroselective Pictet-Spengler
reaction, the catalytic enantioselective variants have only been
developed in recent decades[4]
.
In 2004, Jacobsen et al. reported the first organocatalytic
asymmetric Pictet-Spengler reaction of N-acyliminium ions
with up to 95% ee using a chiral thiourea as the catalyst[5].
They also reported in 2009 that chiral thiourea derivatives in
combination with benzoic acid could cocatalyze the
asymmetric Pictet-Spengler reaction with electronically and
sterically diverse imines to give optically active tetrahedron-β-
carbolines in high ee[6]. BINOL-phosphoric acid catalyzed
Pictet-Spengler reaction required generally disubstituted
tryptamines as the substrates so that the reaction could
provide the corresponding tetrahydro-β-carboline derivatives
in high yields and ee[7]. When SPINOL-phosphoric acids, which
possess geometrically different and more rigid chiral
parameters compared to the classic BINOL-phosphoric acids,
was employed to catalyze the enantioselective Pictet-Spengler
reaction, the optically active tetrahydro-β-carbolines were
afforded in excellent yields and ee values starting directly from
N-protected tryptamine, and the protocol has been applied in
Scheme 1 Catalytic asymmetric Pictet-Spengler reaction
developed by Zhang et al. to further expand the catalysts
types of asymmetric Pictet-Spengler reaction[9]. Several
strategies have been applied to the synthesis of tetrahydro-β-
carbolines in enantiomerically pure form[10-12]. The above
methods with impressive examples demonstrate the power of
asymmetric organocatalysis, however, all the asymmetric
Pictet-Spengler reactions reported so far were catalyzed by
traditional BrØnsted acid. No BrØnsted base has been
reported. So a general and efficient strategy for the catalytic
enantioselective Pictet-Spengler reaction that may tolerate a
broader substrate scope with high enantioselectivity is still in
great demand. Herein, we wish to report the cinchona alkaloid
squaramide catalyzed enantioselective Pictet-Spengler
reaction.
the asymmetric total synthesis of (−)-harmicine[8]
.
H8-BINOL-type chiral imidodiphosphoric acid catalyst was
a.Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of
Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou 310014, P R china. E-mail: weihuizhong@zjut.edu.cn. Fax:
+86 (571)88871087.
† Electronic Supplementary Information (ESI) available: Experimental procedures ,
characterisation data and NMR spectra,HPLC.. CCDC 1476080. See DOI: 10.1039
/x0xx00000x
Initially, we attempted an organic salt that consists of
squaramide-cinchona and achiral BrØnsted acid as the catalyst
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With the optimized reaction conditions identifVieiedw,Arwticele Othnelinne
evaluated the substrate scope of the N-prDoOteI:ct1e0d.10t3ry9p/Cta7mOBin0e26w0i6tDh
Table 1 Optimization of the reaction conditiona
Entry
Catalyst
Solvent
Time(h)
Y(%) b
ee c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18d
19e
20f
21g
22d h
C1
C2
C3
C4
C5
C6
C7
C8
C9
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
PhMe
4-CF3C6H5
xylene
THF
dioxane
Et2O
36
36
28
36
72
72
72
72
72
72
72
72
72
72
72
72
72
72
72
72
72
72
72
91
93
88
73
92
91
/
<5
87
63
71
69
73
71
82
86
93
82
81
87
71
74
82
-72
79
43
-64
72
/
Figure 1 Chiral Cinchona derivatives.
/
81
68
82
78
76
77
86
87
89
40
43
77
71
and the asymmetric Pictet-Spengler reaction proceeded
smoothly to afford moderate enantioselectivities (see
Supporting Information). To our delight, the desired cyclization
product (R)-3a was obtained with 74% ee and 72% yield, when
the reaction was conducted with squaramide-cinchona as the
sole catalyst without the presence of any achiral BrØnsted acid
(Table 1, entry 1). Encouraged by the result, we set up to
identify a chiral alkaloid organocatalyst to achieve the
asymmetric Pictet-Spengler reaction.
ClCH2CH2Cl
CHCl3
PhMe:DCM
PhMe:DCM
PhMe:DCM
PhMe:CHCl3
PhMe:DCM
We continued our investigation by screening quinidine
derived squaramide catalysts C1, C2 and C5 for the reaction
between 1a and 2a in DCM. Gratifyingly the desired product 3a
was obtained with 82% ee and 91% yield with C2 as the
catalyst (Table 1, entry 2). Quinidine derived thiourea catalyst
C7 could also realize the cyclization in acceptable yield, albeit in
a Reactions were performed with 0.05 mmol of 1a, 0.06 mmol of 2a, 20 mol % of
catalyst in 0.5 mL solvent. b Yield of the isolated product. c Determined by HPLC
e
analysis on Chiralcel AD-H column. d PhMe/DCM 1/1 (V/V), PhMe/DCM 1/2
(V/V), f PhMe/DCM 2/1 (V/V), g PhMe:CHCl3 1/1(v/v), h 10mol % of catalyst.
l
ower enantioselectivity (Table 1, entry 7). Employment of
various aldehydes. The representative results are summarized
in Scheme 2. The yields and ee values of tetrahedron-β-
carbolines may be remarkably affected by the type of N-
protecting group of the tryptamine. Best ee value and high
yield was obtained with N-β-napthylmethyl tryptamine (3l),
while N-β-2,6-dimethyl phenyl tryptamine (3x) also gave the
quinine derived bifunctional thiourea C3 or squaramide
catalysts C6 resulted in the predomination of the opposite
enantiomer (S)-3a’ with satisfactory yield and comparable
enantiocontrol (Table 1, entries 3, 6). Quinidine C9 and
quinidine amine C8 were inactive showing the strong H-
bonding donor group should play a major role in the catalysis
(Table 1, entries 8, 9). Since decreased activity as well as
moderate mismatching effect were also observed when the
thiourea was incorporated into catalyst, we turned to the
squaramide-based catalyst C2 for further investigation.
Subsequent optimization suggested that the solvent
remarkably affected the catalytic activity. The use of 1,2-
dichloroethane or chloroform as solvent provided the desired
products both in high yield and enantioselectivity (Table 1,
entries 16, 17), whereas in coordinating solvents such as THF,
dioxane or ethyl ether (Table 1, entries 13-15) relatively
decreased activities were observed. It is worth noting that the
enantioselectivity could be improved when Toluene and DCM
were used as the mixed solvent (Table 1, entry 18), while the
combination of toluene and chloroform as the co-solvent could
not improve the enantioselectivity (Table 1, entry 21).
excellent result with 99% ee and 82% yield. For substrates (3b
,
3d) bearing an electron-withdrawing group in the para position
of the aromatic ring, the reactions occurred readily to give the
desired products in high yields and better enantioselectivities
than substrates possessing electron-withdrawing groups (3c
,
3e). The ortho-substituents on aryl ring resulted in decreased
yields and gave high yield and 83% ee (3i). When N-β-
napthylmethyl tryptamine was treated with various aromatic
aldehydes in the para-position, the desired products were
obtained with lower enantioelectivities than benzaldehyde
(3m-3q). For substitutes bearing a halogen atom (3o-3q) in the
para position of the benzaldehyde, the reactions gave rise to
the target products with a declining ee values along with an
increase of halogen atom radius. Furthermore, aliphatic
aldehyde reacted with N-β-napthylmethyl tryptamine giving a
much better ee (87%-92%) than aromatic ones (3r-3t). The
absolute configuration of product was assigned to be R by
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comparing the optical rotation of 3u with literatures[8,13], while attack by N-β-phenyl tryptamine on the 2’ (FiguVrieew3A)rticvlieaOntlhinee
3i and 3j were assigned S configuration.
TS23, was the first step, which need to DcOoIs:t10o.1f01398/.C77kOcBa0l2/6m0o6Dl.
The dehydration of TS34 to form imine TS5 (Figure 2) is a
significant step. At this point, the dehydration process is
finished,
Scheme 3 Mechanistic Hypothesis.
following the cyclization reaction. The key enantio-
differentiated cyclization then occur via two possible pathways
(see TS56, Figure 2). As observed in the profile, TS56-R follows a
a Reactions were performed with 0.05 mmol of 1, 0.06 mmol of 2, 20 mol % of
c
catalyst C2 in 0.5 mL toluene:CH2Cl2 1/1(V/V). b Yield of the isolated product.
Determined by HPLC analysis on Chiralcel AD-H or OD-H column.
Scheme 2 Scope of the Pictet-Spengler reaction a b c
accordingly.
A
plausible reaction mechanism for the
asymmetric Pictet-Spengler reaction is depicted in Scheme 3
with 3a as the model substrate[14]. Firstly, 2a was combined by
the hydrogen bonds of the catalyst, then nucleophilic attack of
1a to the activated 2’ forms intermediate 3. Elimination of one
molecule of water would generate an ion pair 5, which
undergoes intramolecular Mannich reaction to form 6. Proton
shift in 6 yields product 3a and release catalyst 2C.
In order to rationalize the mechanistic pathway and the
origin of the enantioselectivity, density functional theory (DFT)
calculations were carried out with GAUSSIN 09 program.
In this initial process, a hydrogen bond is formed between
the catalyst and aldehyde group (see 2’, Figure 2). Nucleophilic
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Figure 3 Detailed hydrogen bond distance of TS56-R/S(down)
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DOI: 10.1039/C7OB02606D
Figure 2 DFT M062x/6-31G(p,d) reaction energy profile.
path with an energy barrier around 3.2 kcal/mol lower than based on DFT calculations. Further application of the
other one (TS56-s, Figure 2). Such energetic differences are asymmetric Pictet-Spengler reaction is currently ongoing.
related to the geometric constrictions imposed by the relative
positions of N-β-phenyl tryptamine fixed by hydrogen bonding.
As a consequence, the hydrogen bonding interaction between
Experimental
tryptmine and catalyst is different in TS56-R and TS56-s (for TS56-R,
dN…H =1.69; TS56-R, dN…H=1.72, see Figure 3). The lower energy
of the fixed conformation of TS56-R as a result of the
bifunctional design of the catalyst is responsible for the
enantioselectivity. Evolution of the transition state results in
General remarks
All reactions were carried out in oven-dried glassware with
magnetic stirring under air unless otherwise mentioned. All
other reagents were used without purification as commercially
available. All reactions were monitored by thin layer
chromatography. Purification of reaction products were
carried out by flash chromatography on silica gel. Chemical
yields refer to pure isolated substances. Solvents were purified
and dried according to standard methods prior to use.
Powdered 4Å molecular sieves were activated at 200 °C for 2
h. 1H NMR spectra were recorded on 500 MHz or 600 MHz
spectrometer. The chemical shifts were reported relative to
internal standard TMS (0) in CDCl3. The following
abbreviations may be used to describe peak patterns where
appropriate: br=broad, s=singlet, d=doublet, t=triplet,
q=quartet, m=multiplet. 13C NMR spectra were recorded on
125 MHz or 150 MHz spectrometer, referred to the internal
species
6 in which the C-C bond is already formed. Species 6-S
and 6-R are closed to the final product 3a and only differ form
it in a proton transfer from indole to the squaramide, followed
by a bond isomerization. The finally product 3a-R is more
stable than 3a-S (lower 1.8 kcal/mol calculated by DFT, see
Supporting Information).
Conclusions
In conclusion, we have presented a novel, mild and facile
synthesis of the chiral tetrahydro-β-carline via catalytic
asymmetric Pictet-Spengler reaction. The easily available
cinchona alkaloid squaramide catalyst C2 showed high
efficiency, affording the desired products in good to excellent
yields and ee. A plausible reaction mechanism is also proposed
solvent signals (77.0 for CDCl3). Analytical HPLC was recorded
on a HPLC machine equipped with Agilent 1100 series
quaternary pump with a UV diode array detector. The chiral
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stationary phase was Daicel Chiralcel AD-H and OD-H MHz, CDCl3) δ 2.42(s, 3H), 2.73-2.77(m, 1H), 2.83-V2ie.w8A7r(timcle,O1nHlin)e,
DOI: 10.1039/C7OB02606D
column.Optical rotations were determined using a Rudolph 2.94-2.99(m, 1H), 3.30-3.33(m, 1H), 3.55(d, J=13.8Hz, 1H),
Autopol V polarimeter at 25 °C.
General procedure for the enantioselective Pictet-Spengler
reaction
4.09(d, J=13.8Hz, 1H), 4.71(s, 1H), 7.13-7.18(m, 2H), 7.21-
7.23(m, 1H), 7.24(d, J=7.8Hz, 1H), 7.32(s, 1H), 7.40(d, J=7.8Hz,
2H), 7.49-7.54(m, 2H), 7.56-7.58(m, 2H), 7.82(s, 1H), 7.85-
7.89(m, 3H). 13C NMR (150 MHz, CDCl3) δ 138.34, 137.88,
137.33, 136.32, 135.08, 133.39, 132.82, 129.52, 129.06,
127.92, 127.73, 127.29, 127.28, 127.21, 125.97, 125.54,
121.50, 119.38, 118.34, 110.85, 108.96, 64.39, 58.48, 48.36,
21.25, 21.22.
A mixture of N-protected tryptamine
1 (0.05 mmol),
aldehyde (0.06 mmol), catalyst C2(20% mol), 4 Å molecular
2
sieves (0.1-0.2g, powdered) in 0.5 mL toluene and DCM was
stirred at room temperature. The reaction was monitored with
TLC. After the reaction was completed, the reaction mixture
was directly purified by flash column chromatography (ethyl
acetate / petroleum ether = 1/15 to 1/10, with 2% TEA) to give
(R)-2-benzyl-1-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-
b]indole-(3d)
the desired product 3.
This product was obtained in 89% yield as a white solid after
chromatography and 84% ee as determined by HPLC [Daicel
Chiralpak AD-H, n-hexane/i-propanol=90:10, 0.8mL/min,
λ=254nm, t (major)=10.8 min, t (minor)=13.8 min]. [α]D25= -
(R)-2-benzyl-1-phenyl-2,3,4,9-tetrahydro-1-H-pyrido[3,4-b]indole-
(3a)
This product was obtained in 93% yield as a white solid after
chromatography and 89% ee as determined by HPLC [Daicel
Chiralpak AD-H, n-hexane/i-propanol= 90:10, 0.8mL/min,
λ=254nm, t(major)=10.87min, t(minor)=12,25min]. [α]D25= -
43.3(c=0.9,
CH2Cl2);
HRMS
(ESI-TOF)
calcd
for
1
C24H22FN2[M+H]+
:
357.1756; Found: 353.1760. H NMR (500
MHz, CDCl3) δ 2.68-2.73(m, 1H), 2.81-2.86(m, 1H), 2.90-
2.96(m, 1H), 3.22-3.27(m, 1H), 3.39(d, J= 8.5Hz, 1H), 3.89(d,
J=8.5Hz, 1H), 4.67(s, 1H), 7.04-7.08(m, 2H), 7.10-7.15(m, 2H),
7.20-7.23(m, 1H), 7.26-7.28(m, 1H), 7.32-7.36(m, 4H), 7.39-
7.43(m, 2H), 7.53(d, J=6.0Hz, 1H). 13C NMR (125 MHz, CDCl3) δ
163.50, 161.54, 139.39, 137.24, 136.31, 134.47, 130.59,
130.53, 128.68, 128.29, 127.16, 127.02, 121.67, 119.47,
118.37, 115.70, 115.53, 110.82, 109.18, 63.61, 58.18, 48.16,
21.03. IR: 705.58, 747.30, 896.02, 1265.33, 1421.86, 2305.65,
2685.53, 2986.91, 3054.20, 3943.98.
63.1(c=0.97,
CH2Cl2);
HRMS
(ESI-TOF)
calcd
for
C24H23N2[M+H]+:339.1856; Found: 339.1862. 1H NMR (500
MHz, CDCl3) δ2.65-2.70(m, 1H), 2.79-2.83(m, 1H), 2.90-2.96(m,
1H), 3.23-3.27(m, 1H), 3.37(d, J=13.5Hz, 1H), 3.90(d, J=13.5Hz,
1H), 4.65(s, 1H), 7.10-7.14(m, 2H), 7.18-7.19(m, 1H), 7.25-
7.28(m, 1H), 7.32-7.35(m, 3H), 7.36-7.39(m, 4H), 7.47(m, 2H),
7.53-7.54(m, 1H). 13C NMR (125 MHz, CDCl3) δ 141.46, 139.57,
136.29, 134.86, 129.02, 128.76, 128.70, 128.23, 128.08,
127.21, 126.92, 121.49, 119.35, 118.30, 110.78, 108.95, 64.60,
58.33, 48.35, 21.18.
(R)-2-benzyl-1-(4-chlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-
b]indole-(3e)
(R)-2-benzyl-1-(4-(trifluoromethyl)phenyl)-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole-(3b)
This product was obtained in 83% yield as a white solid after
chromatography and 72% ee as determined by HPLC [Daicel
Chiralpak AD-H, n-hexane/i-propanol= 90:10, 0.8mL/min,
λ=225nm, t (major)=11.3 min, t (minor)=13.4 min]. [α]D25= -
35.8(c=1.0, CH2Cl2); HRMS (ESI-TOF) calcd for C24H22ClN2
[M+H]+: 373.1466; Found: 373.1475. 1H NMR (500 MHz, CDCl3)
δ 2.68-2.70(m, 1H), 2.80-2.84(m, 1H), 2.89-2.91(m, 1H), 3.21-
3.25(m, 1H), 3.39(d, J=8.5Hz, 1H), 3.86(d, J=8.5Hz, 1H), 4.64(s,
1H), 7.12-7.16(m, 2H), 7.20-7.23(m, 1H), 7.27-7.30(m, 1H),
7.34-7.36(m, 6H), 7.38-7.40(m,2H), 7.54(d, J=7.5Hz, 1H). 13C
NMR (125 MHz, CDCl3) δ 140.08, 139.24, 136.32, 134.11,
133.78, 130.32, 128.92, 128.66, 128.30, 127.10, 127.05,
121.72, 119.49, 118.37, 110.83, 109.24, 63.64, 58.23, 48.09,
20.99.
This product was obtained in 95% yield as a white solid after
chromatography and 80% ee as determined by HPLC [Daicel
Chiralpak AD-H, n-hexane/i-propanol=90:10, 0.8mL/min,
λ=225nm, t (major)=8.6 min, t (minor)=10.6 min]. [α]D25= -
42.3(c=1.4, CH2Cl2); HRMS (ESI-TOF) calcd for C25H22F3N2
[M+H]+: 407.1730; Found: 407.1742. 1H NMR (600 MHz, CDCl3)
δ2.69-2.73(m, 1H), 2.82-2.85(m, 1H), 2.89-2.94(m, 1H), 3.21-
3.32(m, 1H), 3.43(d, J=13.8Hz, 1H), 3.84(d, J=13.8Hz, 1H),
4.73(s, 1H), 7.11-7.16(m, 2H), 7.21(d, J=7.2Hz, 1H), 7.25-
7.35(m, 1H), 7.54(s, 1H), 7.56-7.64(m, 4H). 13C NMR (150 MHz,
CDCl3) 145.85, 139.12, 136.39, 133.60, 130.43, 130.21, 129.33,
128.69, 128.38, 127.18, 127.07, 125.75, 125.73, 125.01,
123.21, 121.90, 119.61, 118.47, 110.91, 109.48, 63.78, 58.38,
48.01, 20.91.
(R)-2-benzyl-1-(2-fluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-
b]indole-(3f)
(R)-2-benzyl-1-(p-tolyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-
(3c)
This product was obtained in 82% yield as a white solid after
chromatography and 32% ee as determined by HPLC [Daicel
This product was obtained in 76% yield as a white solid after
chromatography and 74% ee as determined by HPLC [Daicel
Chiralpak AD-H, n-hexane/i-propanol
λ=254nm, t (major)=13.1 min, t (minor) =17.9 min]. [α]D25= -
Chiralpak AD-H, n-hexane/i-propanol= 70:30, 0.8mL/min
λ=225nm, t (major)=6.9 min, t (minor)=8.0 min]. [α]D25= -
29.4(c=1.0, CH2Cl2); HRMS (ESI-TOF) calcd for
,
= 95:5, 0.8mL/min,
1
C24H22FN2[M+H]+:357.1757; Found: 353.1763. H NMR (500
MHz, CDCl3) δ 2.72-2.73(m, 1H), 2.83-2.86(m, 1H), 2.92-
2.94(m, 1H), 3.24-3.27(m, 1H), 3.51(d, J=8.5Hz, 1H), 3.90(d,
57.3(c=1.0,
CH2Cl2);
HRMS
(ESI-TOF)
calcd
for
C24H25N2[M+H]+:353.1956; Found: 353.1962. 1H NMR (600
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Journal Name
J=8.5Hz, 1H), 5.22(s, 1H), 7.12-7.20(m, 4H), 7.24-7.25(m, 1H), J=4.8Hz, 1H), 9.63(s, 1H). 13C NMR (150 MHz, CDCl3) δ 162.55,
View Article Online
DOI: 10.1039/C7OB02606D
7.28-7.32(m, 2H), 7.34-7.41(m, 4H), 7.48(s, 1H), 7.50-7.53(m, 148.39, 139.23, 137.57, 136.85, 134.03, 128.59, 128.43,
1H), 7.55(d, J=6.0Hz 1H). 13C NMR (125 MHz, CDCl3) δ 162.38, 127.11, 126.98, 122.76, 122.37, 121.46, 119.13, 118.34,
160.43, 136.29, 130.59, 129.41, 128.70, 128.25, 126.98, 111.01, 108.37, 65.77, 59.10, 48.42, 21.31. IR: 705.37, 739.22,
124.74, 124.71, 121.67, 119.42, 118.29, 115.51, 115.34, 896.07, 1141.22, 1200.29, 1265.36, 1421.84, 1681.12, 2305.57,
110.82, 109.64, 58.45, 56.28, 47.80, 20.94.
2987.00, 3051.31, 3445.91.
(R)-2-benzyl-1-(2-methoxyphenyl)-2,3,4,9-tetrahydro-1H-
(S)-2-benzyl-1-(thiophen-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-
pyrido[3,4-b]indole-(3g)
b]indole-(3j)
This product was obtained in 77% yield as a white solid after This product was obtained in 79% yield as a white solid after
chromatography and 58% ee as determined by HPLC [Daicel chromatography and 65% ee as determined by HPLC [Daicel
Chiralpak AD-H, n-hexane/i-propanol=98:2, 0.8mL/min, Chiralpak AD-H, n-hexane/i-propanol=70:30, 0.8mL/min,
λ=254nm, t (major) = 26.1 min, t (minor) =29 min]. [α]D25= - λ=225nm, t (major)=7.8 min, t (minor)=11.2 min]. [α]D25= -
32.1(c=1.0,
CH2Cl2);
HRMS
(ESI-TOF)
calcd
for 16.7(c=1.0, CH2Cl2); HRMS (ESI-TOF) calcd for C22H21N2S
C25H25ON2[M+H]+:369.1957; Found: 353.1761. 1H NMR (500 [M+H]+: 345.1308; Found: 345.1302. 1H NMR (500 MHz, CDCl3)
MHz, CDCl3) δ 2.64-2.69(m, 1H), 2.76-2.79(m, 1H), 2.86- δ 2.72-2.77(m, 1H), 2.82-2.91(m, 2H), 3.26-3.31(m, 1H), 3.50(d,
2.89(m, 1H), 3.24-3.26(m, 1H), 3.40(d, J=13.5Hz, 1H), 3.88(d, J=14.0Hz, 1H), 4.02(d, J=14.0Hz, 1H), 5.50(s, 1H), 7.02-7.03(m,
J=13.5Hz, 1H), 3.95(s, 3H), 5.26(s, 1H), 6.91-6.94(m,1H), 6.98- 1H), 7.12-7.19(m, 3H), 7.25(d, J=7.5Hz, 1H), 7.30-7.34(m, 2H),
7.00(m, 1H), 7.04-7.10(m, 2H), 7.18-7.20(m, 1H), 7.23-7.27(m, 7.36(t, J=7.5Hz, 2H), 7.46(d, J=6.0Hz, 3H), 7.53(d, J=7.5Hz). 13C
2H), 7.30-7.33(m, 2H), 7.36(d, J=6.0Hz, 2H), 7.48-7.50(m, 1H), NMR (125 MHz, CDCl3) δ 145.97, 139.24, 136.21, 133.94,
7.57-7.59(m, 1H), 7.67(b, 1H). 13C NMR (125 MHz, CDCl3) δ 128.72, 128.28, 127.23, 127.03, 126.26, 126.24, 126.19,
157.50, 138.43, 136.29, 133.59, 131.41, 128.70, 128.41, 128.23, 121.71, 119.41, 118.47, 110.88, 108.58, 59.17, 58.20, 47.86,
127.25, 127.19, 121.98, 120.74, 119.71, 118.67, 112.42, 20.81.
111.29, 111.14, 105.51, 58.85, 56.40, 55.70, 48.29, 21.07.
(R)-2-benzyl-1-cyclohexyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-
(R)-2-benzyl-1-(4-nitrophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-
b]indole-(3k)
b]indole-(3h)
This product was obtained in 82% yield as a white solid after
This product was obtained in 91% yield as a light yellow solid chromatography and 78% ee as determined by HPLC [Daicel
after chromatography and 50% ee as determined by HPLC Chiralpak AD-H, n-hexane/i-propanol=90:10, 0.8mL/min,
25
[Daicel
Chiralpak
AD-H,
n-hexane/i-propanol=70:30, λ=225nm, t (minor)=5.9 min, t (major)=6.4 min]. [α]D
=
0.8mL/min, λ=225nm, t (major)=7.2 min, t (minor)=8.1 min]. +21.89(c=1.0, CH2Cl2); HRMS (ESI-TOF) calcd for C24H29N2
[α]D25=-12.9(c=1.2, CH2Cl2); HRMS (ESI-TOF) calcd for [M+H]+: 345.2318; Found: 345.2322. 1H NMR (600 MHz, CDCl3)
1
C24H22ON3[M+H]+: 384.1667; Found: 384.1669. H NMR (500 δ 0.88-0.95(m, 1H), 1.05-1.10(m, 2H), 1.14-1.30(m, 5H), 1.68-
MHz, CDCl3) δ 2.73-2.78(m, 1H), 2.87-2.91(m, 2H), 3.18- 1.87(m, 7H), 2.30(d, J=13.2Hz, 1H), 2.53-2.57(m, 1H), 2.98-
3.23(m, 1H), 3.50(d, J=13.5Hz, 1H), 3.81(d, J=13.5Hz, 1H), 3.05(m, 2H), 3.23(d, J=9.0Hz, 1H), 3.31-3.34(m, 1H), 3.610(d,
4.79(s,1H), 7.13-7.18(m, 2H), 7.23-7.25(m, 1H), 7.29-7.30(m, J=13.2Hz, 1H), 3.76(d, J= 13.2Hz, 1H), 7.14-7.18(m, 1H), 7.18-
1H), 7.35-7.39(m, 5H), 7.56(d, J=7.5Hz 1H), 7.58(d, J=7.5Hz, 7.21(m, 1H), 7.27(t, J=7.2Hz, 1H), 7.32-7.38(m, 5H), 7.56(d,
2H), 8.18(d, J=9.0Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 149.47, J=7.8Hz, 1H), 7.67(s, 1H). 13C NMR (150 MHz, CDCl3) δ 140.13,
147.62, 138.79, 136.44, 132.67, 129.72, 128.65, 128.40, 135.57, 134.56, 129.14, 128.14, 127.33, 126.92, 121.40,
127.27, 126.95, 123.86, 122.06, 119.67, 118.49, 110.93, 119.21, 118.14, 110.59, 107.70, 104.38, 62.15, 57.59, 43.79,
109.71, 63.06, 58.38, 47.61, 20.59. IR: 705.29, 739.04, 896.01, 42.72, 41.93, 31.17, 31.00, 27.12, 26.60, 26.54, 26.45, 26.41,
1265.35, 1349.48, 1421.74, 1524.46, 1635.76, 2305.46, 25.73, 17.15.
2987.06, 3054.44, 3451.23.
(R)-2-(naphthalen-2-ylmethyl)-1-phenyl-2,3,4,9-tetrahydro-1H-
(S)-2-benzyl-1-(pyridin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-
pyrido[3,4-b]indole -(3l)
b]indole -(3i)
This product was obtained in 90% yield as a white solid after
This product was obtained in 76% yield as a yellow solid after chromatography and 99% ee as determined by HPLC [Daicel
chromatography and 83% ee as determined by HPLC [Daicel Chiralpak AD-H, n-hexane/i-propanol=70:30, 0.8mL/min,
Chiralpak AD-H, n-hexane/i-propanol= 70:30, 0.8mL/min, λ=225nm, t (major)=7.6 min, t (minor)=13.2 min]. [α]D25= -
λ=225nm, t (minor)=8.9 min, t (major)=28.8 min]. [α]D25= - 61.89(c=1.0, CH2Cl2); HRMS (ESI-TOF) calcd for C28H25N2
63.2(c=1.0, CH2Cl2); HRMS (ESI-TOF) calcd for C23H22N3 [M+H]+: 389.2012; Found: 389.2018. 1H NMR (600 MHz, CDCl3)
[M+H]+: 340.1808; Found: 340.1798. 1H NMR (600 MHz, CDCl3) δ 2.75-2.76(m, 1H), 2.86-2.91(m, 2H), 3.26-3.29(m, 1H), 3.87(d,
δ 2.76-2.80(m, 1H), 2.89-2.91(m, 1H), 3.00-3.05(m, 1H), 3.32- J=13.2Hz, 1H), 4.34(d, J=13.8Hz, 1H), 4.76(s, 1H), 7.13-7.19(m,
3.36(m, 1H), 3.58(d, J=14.4Hz, 1H), 4.02(d, J=14.4Hz, 1H), 2H), 7.23(d, J=7.2Hz, 1H), 7.35(s, 1H), 7.37-7.38(m, 1H), 7.39-
5.11(s, 1H), 7.15-7.20(m, 2H), 7.22-7.24(m, 1H), 7.32-7.35(m, 7.45(m, 3H), 7.47-7.49(m, 3H), 7.49-7.51(m, 1H), 7.57(d,
2H), 7.39(t, J=7.2, 7.8Hz, 2H), 7.48(d, J=13.2Hz, 2H), 7.60(d, J= J=7.2Hz, 1H), 7.61(d, J=7.2Hz, 1H), 7.81(d, J=8.4Hz, 1H), 7.87(d,
7.2Hz, 1H), 7.75-7.78(m, 1H), 7.91(d, J=7.8Hz, 1H), 8.39(d, J=7.8Hz, 1H), 8.08(d, J=8.4Hz, 1H). 13C NMR (150 MHz, CDCl3) δ
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
141.34, 136.31, 135.00, 134.71, 133.82, 132.40, 129.42, 130.63, 128.05, 127.76, 127.72, 127.32, 127V.2iew1,Arti1cl2e7O.n0lin8e,
DOI: 10.1039/C7OB02606D
128.63, 128.39, 128.18, 127.77, 127.22, 127.19, 125.55, 126.07, 125.66, 121.75, 119.53, 118.44, 115.75, 115.60,
125.28, 124.69, 121.58, 119.40, 118.35, 110.85, 109.39, 65.22, 110.89, 109.27, 63.51, 58.38, 48.05, 20.96.
56.59, 48.19, 20.92. IR: 705.33, 746.45, 896.01, 1142.43,
(R)-1-(4-chlorophenyl)-2-(naphthalen-2-ylmethyl)-2,3,4,9-
tetrahydro-1H-pyrido[3,4-b]indole-(3p)
1205.67, 1265.28, 1421.71, 1683.23, 2305.52, 2987.12,
3054.40, 3446.79.
This product was obtained in 84% yield as a white solid after
chromatography and 31% ee as determined by HPLC [Daicel
Chiralpak AD-H, n-hexane/i-propanol=70:30, 0.8mL/min,
(R)-2-(naphthalen-2-ylmethyl)-1-(4-(trifluoromethyl)phenyl)-
2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-(3m)
This product was obtained in 92% yield as a white solid after λ=225nm, t (major) =7.5 min, t (minor)=12.1 min]. [α]D25= -
chromatography and 69% ee as determined by HPLC [Daicel 35.8(c=1.0, CH2Cl2); HRMS (ESI-TOF) calcd for C28H24ClN2
Chiralpak AD-H, n-hexane/i-propanol=80:20, 0.8mL/min, [M+H]+: 423.1623; Found: 423.1620. 1H NMR (500 MHz, CDCl3)
λ=225nm, t (major)=6.6 min, t (minor)=12.5 min]. [α]D25= - δ 2.77-2.18(m, 1H), 2.86-2.88(m, 1H), 3.28-3.32(m, 1H), 3.60(d,
51.89(c=1.2, CH2Cl2); HRMS (ESI-TOF) calcd for C29H24N2F3 J=13.5Hz, 1H), 4.04(d, J=13.5Hz, 1H), 4.71(s, 1H), 7.17-7.23(m,
1
[M+H]+: 457.1852; Found: 457.1858 H NMR (600 MHz, CDCl3) 2H), 7.24-7.26(m, 1H), 7.31(s, 1H), 7.40-7.44(m, 4H), 7.51-
δ 2.72-2.76(m, 1H), 2.85-2.88(m, 1H), 2.92-2.95(m, 1H), 3.24- 7.57(m, 3H), 7.60-7.62(m, 1H), 7.82(s, 1H), 7.88(t, J=8.5,
3.27(m, 1H), 3.46(d, J=13.8Hz, 1H), 3.87(d, J=13.8Hz, 1H), 10.0Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 140.07, 136.86,
4.76(s, 1H), 7.14-7.19(m, 2H), 7.24(d, J=7.2Hz, 1H), 7.30- 136.32, 133.97, 133.76, 133.33, 132.81, 130.34, 128.89,
7.32(m, 1H), 7.36-7.38(m, 4H), 7.57(s, 1H), 7.59(d, J=8.4Hz, 127.99, 127.69, 127.65, 127.26, 127.12, 126.99, 126.01,
2H), 7.65(d, J=7.8Hz, 2H). 13C NMR (150 MHz, CDCl3) δ 145.85, 125.60, 121.73, 119.49, 118.37, 110.84, 109.27, 63.45, 58.36,
139.12, 136.39, 133.60, 130.43, 130.21, 129.33, 128.69, 47.89, 20.85.
128.38, 127.18, 127.07, 125.75, 125.73, 125.01, 123.21,
121.90, 119.61, 118.47, 110.91, 109.48, 63.78, 58.38, 48.01,
20.91.
(R)-1-(4-bromophenyl)-2-(naphthalen-2-ylmethyl)-2,3,4,9-
tetrahydro-1H-pyrido[3,4-b]indole-(3q)
This product was obtained in 87% yield as a white solid after
chromatography and 23% ee as determined by HPLC [Daicel
Chiralpak AD-H, n-hexane/i-propanol=90:10, 0.8mL/min,
λ=225nm, t (major)=13.9 min, t (minor)=29.1 min]. [α]D25= -
31.4(c=1.2, CH2Cl2); HRMS (ESI-TOF) calcd for C28H24BrN2
[M+H]+: 467.1023; Found: 467.1020. 1H NMR (600 MHz, CDCl3)
δ 2.53-2.56(m, 1H), 2.63-2.69(m, 2H), 3.02-3.05(m, 1H), 3.37-
3.41(m, 1H), 3.75-3.79(m, 1H), 4.56(s, 1H), 6.90-6.96(m, 2H),
6.98-7.05(m, 2H), 7.25-7.28(m, 3H), 7.34-7.36(m, 3H), 7.40-
7.43(m, 2H), 7.53(d, J=10.2Hz, 1H), 7.60-7.64(m, 3H).13C NMR
(150 MHz, CDCl3) δ 145.82, 136.73, 136.42, 133.46, 133.37,
132.89, 129.37, 128.12, 127.76, 127.71, 127.36, 127.11,
126.98, 126.12, 125.73, 121.94, 119.64, 118.49, 110.93,
109.56, 63.63, 58.56, 47.86, 20.79.
(R)-2-(naphthalen-2-ylmethyl)-1-(p-tolyl)-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole-(3n)
This product was obtained in 81% yield as a white solid after
chromatography and 76% ee as determined by HPLC [Daicel
Chiralpak AD-H, n-hexane/i-propanol=95:5, 0.8mL/min,
λ=254nm, t (major)=12.8 min, t (minor) =21.3 min]. [α]D25= -
39.1(c=1.1, CH2Cl2); HRMS (ESI-TOF) calcd for C29H27N2 [M+H]+:
403.2152; Found: 403.2159. 1H NMR (600 MHz, CDCl3) δ
2.39(s, 3H), 2.65-2.70(m, 1H), 2.80-2.83(m, 1H), 2.92-2.94(m,
1H), 3.24-3.27(m, 1H), 3.69(d, J=7.8Hz, 1H), 3.92(d, J=7.8Hz,
1H), 4.64(s, 1H), 7.12-7.15(m, 2H), 7.20(d, 7.2Hz, 3H), 7.26-
7.29(m, 2H), 7.33-7.39(m, 7H), 7.54(d, J=7.2Hz, 1H). 13C NMR
(150 MHz, CDCl3) δ 139.68, 138.34, 137.80, 136.28, 135.17,
129.46, 128.97, 128.72, 128.23, 127.26, 126.89, 121.44,
119.32, 118.29, 110.79, 108.87, 64.42, 58.28, 48.46, 21.28,
21.21.
(R)-1-cyclohexyl-2-(naphthalen-2-ylmethyl)-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole-(3r)
This product was obtained in 91% yield as a white solid after
chromatography and 92% ee as determined by HPLC [Daicel
(R)-1-(4-fluorophenyl)-2-(naphthalen-2-ylmethyl)-2,3,4,9-
tetrahydro-1H-pyrido[3,4-b]indole-(3o)
Chiralpak AD-H, n-hexane/i-propanol=98:2, 0.8mL/min,
25
This product was obtained in 93% yield as a white solid after
chromatography and 87% ee as determined by HPLC [Daicel
Chiralpak AD-H, n-hexane/i-propanol=70:30, 0.8mL/min,
λ=225nm, t (major)=7.3 min, t (minor)=12.2 min]. [α]D25= -
λ=225nm, t (major)=16.1 min, t (minor)=17.7 min]. [α]D
=
+51.4(c=1.1, CH2Cl2); HRMS (ESI-TOF) calcd for C28H31N2
[M+H]+: 395.2433; Found: 395.2428. 1H NMR (600 MHz, CDCl3)
δ 0.81-0.87(m, 2H), 0.95-0.99(m, 1H), 1.06-1.25(m, 4H), 1.60-
1.75(m, 6H), 2.29(d, J=13.2Hz, 1H), 2.51-2.54(m, 1H), 2.95-
3.06(m, 2H), 3.19(m, 1H), 3.31-3.36(m, 1H), 3.71(d, J=13.2Hz,
1H), 3.86(d, J=13.2Hz, 1H), 7.10-7.12(m, 1H), 7.15-7.17(m, 1H),
7.30(d, J=7.8Hz, 1H), 7.41-7.45(m, 2H), 7.53(d, J=8.4Hz, 1H),
7.58-7.63(m, 3H), 7.74-7.76(m, 1H), 7.79-7.82(m, 2H). 13C NMR
(150 MHz, CDCl3) δ 137.71, 135.60, 134.52, 133.32, 132.86,
127.79, 127.73, 127.70, 127.43, 127.36, 125.90, 125.52,
121.43, 119.24, 118.17, 110.61, 107.67, 61.96, 57.71, 44.02,
59.3(c=1.2,
CH2Cl2);
HRMS
(ESI-TOF)
calcd
for
C28H24FN2[M+H]+:407.1847; Found: 407.1843. H NMR (600
MHz, CDCl3) δ 2.76-2.80(m, 1H), 2.85-2.89(m, 1H), 2.92-
2.97(m, 1H), 3.28-3.32(m, 1H), 3.59(d, J=13.2Hz, 1H), 4.05(d,
J=13.2Hz. 1H), 4.73(s, 1H), 7.10-7.13(m, 2H), 7.15-7.21(m, 2H),
7.25(d, J=7.2Hz, 1H), 7.30(s, 1H), 7.45-7.47(m, 2H), 7.51-
7.55(m, 3H), 7.59(d, J=7.8Hz, 1H), 7.81(s, 1H), 7.86-7.90(m,
3H). 13C NMR (150 MHz, CDCl3) δ 163.39, 161.75, 137.28,
137.26, 137.04, 136.35, 134.39, 133.39, 132.86, 130.68,
1
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Organic & Biomolecular Chemistry
Page 8 of 9
ARTICLE
Journal Name
42.72, 31.18, 31.01, 29.78, 26.57, 26.46, 26.40, 17.21. IR: 125.25, 124.66, 121.55, 119.38, 118.31, 110.82, 1V0ie9w.3A6rti,cl7e7O.n2li9ne,
705.42, 738.60, 895.95, 1265.30, 1421.81, 1636.01, 2305.42, 77.03, 76.78, 65.19, 56.55, 48.15, 20.88.DOI: 10.1039/C7OB02606D
2986.89, 3054.32, 3455.35.
(R)-2-(2,6-dimethylbenzyl)-1-phenyl-2,3,4,9-tetrahydro-1H-
(R)-1-isopropyl-2-(naphthalen-2-ylmethyl)-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole-(3v)
pyrido[3,4-b]indole-(3s)
This product was obtained in 82% yield as a white solid after
This product was obtained in 88% yield as a white solid after chromatography and 82% ee as determined by HPLC [Daicel
chromatography and 85% ee as determined by HPLC [Daicel Chiralpak AD-H, n-hexane/i-propanol= 90:10, 0.8mL/min,
Chiralpak OD-H, n-hexane/i-propanol=80:20, 0.8mL/min, λ=225nm, t (major)=8.3 min, t (minor)=7.6 min]. [α]D25= -
25
λ=225nm, t (major)=7.1 min, t (minor)=8.1 min]. [α]D
=
42.7(c=1.0, CH2Cl2); HRMS (ESI-TOF) calcd for C28H25N2
+38.8(c=1.0, CH2Cl2); HRMS (ESI-TOF) calcd for C25H27N2 [M+H]+: 367.2142; Found: 367.2147. 1H NMR (500 MHz, CDCl3)
[M+H]+: 355.2123; Found: 355.2129. 1H NMR (600 MHz, CDCl3) δ 2.98(m, 2H), 3.04-3.08(m, 1H), 3.35-3.39(m, 1H), 3.78(s, 3H),
δ 0.88-1.10(m, 6H), 1.20-1.25(m, 1H), 2.00(d, J=6.6Hz, 1H), 3.82(s, 3H), 3.90-3.98(m, 2H), 5.54(s, 1H), 6.41-6.43(m, 1H),
2.52(d, J=15.6Hz, 1H), 2.97-3.32(m, 3H), 3.68-3.89(m, 2H), 6.53(m, 1H), 7.12-7.17(m, 2H), 7.21-7.27(m, 2H), 7.31-7.38(m,
7.11-7.18(m, 2H), 7.32(d, J=7.8Hz, 1H), 7.43-7.45(m, 2H), 3H), 7.44(m, 5H), 7.55-7.59(m, 3H), 7.91(br, 1H), 8.10(d,
7.54(d, J=7.2Hz, 1H), 7.59-7.65(m, 2H), 7.75-7.81(m, 2H). 13C J=9.0Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 160.71, 158.67,
NMR (150 MHz, CDCl3) δ 137.67, 135.63, 134.66, 133.30, 136.27, 132.92, 130.94, 130.02, 129.69, 128.23, 127.43,
132.83, 127.70, 127.66, 127.41, 125.89, 125.51, 121.44, 126.83, 121.57, 119.28, 118.14, 110.88, 108.42, 104.84, 98.43,
119.24, 118.16, 110.62, 107.95, 63.03, 57.85, 44.13, 33.11, 57.22, 55.44, 55.30, 54.94, 46.77, 19.83.
21.04, 20.45, 17.32.
(R)-2-(2,6-dimethylbenzyl)-1-(4-fluorophenyl)-2,3,4,9-tetrahydro-
(R)-1-benzyl-2-(naphthalen-2-ylmethyl)-2,3,4,9-tetrahydro-1H-
1H-pyrido[3,4-b]indole-(3w)
pyrido[3,4-b]indole-(3t)
This product was obtained in 93% yield as a white solid after
This product was obtained in 89% yield as a white solid after chromatography and 81% ee as determined by HPLC [Daicel
chromatography and 87% ee as determined by HPLC [Daicel Chiralpak AD-H, n-hexane/i-propanol=95:5, 0.8mL/min,
Chiralpak AD-H, n-hexane/i-propanol=70:30, 0.8mL/min, λ=225nm, t (major)=12.3 min, t (minor)=13.1 min]. [α]D25= -
25
λ=225nm, t (major)=7.3 min, t (minor)=8.0 min]. [α]D
=
49.7(c=1.0, CH2Cl2); HRMS (ESI-TOF) calcd for C26H26FN2
+42.3(c=1.0, CH2Cl2); HRMS (ESI-TOF) calcd for C29H27N2 [M+H]+: 385.2075; Found: 385.2067. 1H NMR (600 MHz, CDCl3)
[M+H]+: 403.2143; Found: 403.2147. 1H NMR (600 MHz, CDCl3) δ 2.27(s, 6H), 2.69-2.73(m, 1H), 2.79-2.82(m, 2H), 3.07-3.11(m,
δ 2.53-2.57(m, 1H), 2.86-2.93(m, 2H), 3.01-3.04(m, 1H), 3.18- 1H), 3.52(d, J=12.6Hz, 1H), 3.79(d, J=12.6Hz, 1H), 4.56(s, 1H),
3.21(m, 1H), 3.30-3.35(m, 1H), 3.85-3.91(m, 3H), 6.85(s, 1H), 7.01(d, J=7.8Hz, 1H), 7.08-7.15(m, 3H), 7.20(d, J=7.2Hz, 1H),
6.98-7.04(m, 6H), 7.11(s, 1H), 7.15-7.18(m, 3H), 7.31(d, 7.29-7.31(m, 3H), 7.31-7.34(m, 3H), 7,54(d, J=7.2Hz, 1H). 13C
J=7.8Hz, 1H), 7.33-7.37(m, 2H), 7.43-7.45(m, 1H), 7.54(s, 1H), NMR (150 MHz, CDCl3) δ 141.26, 138.61, 136.25, 135.28,
7.62-7.65(m, 2H), 7.71-7.73(m, 1H). 13C NMR (150 MHz, CDCl3) 134.67, 129.69, 128.27, 128.22, 128.01, 127.18, 126.97,
δ 139.21, 135.62, 133.40, 132.86, 129.71, 128.54, 127.98, 121.53, 119.37, 118.32, 110.87, 109.75, 64.87, 52.16, 46.98,
127.84, 127.72, 127.11, 127.08, 127.06, 126.59, 125.94, 20.88, 20.53.
125.58, 121.54, 119.32, 118.20, 110.75, 107.89, 58.35, 57.57,
44.64, 41.22, 18.14.
(R)-1-cyclohexyl-2-(2,6-dimethylbenzyl)-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole -(3x)
(R)-2-(naphthalen-1-ylmethyl)-1-phenyl-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole-(3u)
This product was obtained in 82% yield as a white solid after
chromatography and 99% ee as determined by HPLC [Daicel
This product was obtained in 94% yield as a white solid after Chiralpak OJ-H, n-hexane/i-propanol=98:1.2, 0.8mL/min,
25
chromatography and 74% ee as determined by HPLC [Daicel λ=225nm, t (major)=18.4 min, t (minor)=31.1 min].[α]D
=
Chiralpak AD-H, n-hexane/i-propanol=90:10, 0.8mL/min, +42.7(c=1.0, CH2Cl2); HRMS (ESI-TOF) calcd for C26H33N2
λ=225nm, t (major)=10.4 min, t (minor)=12.5 min]. [α]D25= - [M+H]+: 373.2638; Found: 373.2644. 1H NMR (600 MHz, CDCl3)
62.6(c=1.0, CH2Cl2); HRMS (ESI-TOF) calcd for C28H25N2 δ 0.52-0.54(m, 1H), 0.97-1.06(m, 1H), 1.08-1.14(m, 3H), 1.25-
[M+H]+: 389.2012; Found: 389.2007. 1H NMR (600 MHz, CDCl3) 1.31(m, 1H), 1.60-1.67(m, 5H), 1.98-2.00(m, 1H), 2.27(s, 6H),
δ 2.69-2.74(m, 1H), 2.80-2.91(m, 2H), 3.22-3.26(m, 1H), 3.83(d, 2.60-2.64(m, 1H), 3.04-3.16(m, 3H), 3.39-3.43(m, 1H), 3.52-
J=16.2Hz, 1H), 4.30(d, J=15.6Hz, 1H), 4.73(s, 1H), 7.10-7.16(m, 3.55(m, 1H), 3.85-3.88(m, 1H), 7.02-7.03(m, 2H), 7.09-
2H), 7.21-7.22(m, 1H), 7.32-7.35(m, 2H), 7.36-7.37(m, 1H), 7.10(m,1H), 7.15-7.17(m,1H), 7.19-7.25(m, 1H), 7.35-
7.38-7.41(m, 1H), 7.42-7.48(m, 4H), 7.53-7.55(m, 1H), 7.58(d, 7.37(m,1H), 7.59-7.60(m, 1H), 7.70(s, 1H). 13C NMR (150 MHz,
J=8.4Hz, 1H), 7.77-7.79(d, J=10.2Hz, 1H), 7.84-7.85(d, J=9.6Hz, CDCl3) δ 138.40, 135.80, 135.62, 134.81, 128.02, 127.46,
1H), 8.04-8.06(d, J=10.2Hz, 1H).13C NMR (125 MHz, CDCl3) δ 126.79, 121.33, 119.18, 118.17, 110.61, 107.88, 104.39, 77.32,
141.32, 136.31, 134.97, 134.68, 133.80, 132.38, 129.39, 77.11, 76.89, 59.48, 50.14, 45.02, 42.25, 41.94, 31.00, 30.49,
128.60, 128.36, 128.16, 127.74, 127.20, 127.18, 125.52, 27.13, 26.55, 26.46, 26.29, 26.20, 26.03, 25.74, 20.12, 17.49.
8 | J. Name., 2012, 00, 1-3
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Page 9 of 9
Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
2
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(S)-2-benzyl-6-methoxy-1-phenyl-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole -(3y)
This product was obtained in 93% yield as a white solid after
chromatography and 20% ee as determined by HPLC [Daicel
Chiralpak AD-H, n-hexane/i-propanol=90:10, 0.8mL/min,
λ=225nm, t (major)=15.1 min, t (minor)=21.7 min].[α]D25= -
22.7(c=1.0, CH2Cl2);HRMS (ESI-TOF) calcd for C25H25N2O
[M+H]+: 369.1961; Found: 369.1963. 1H NMR (600 MHz, CDCl3)
δ 2.68-2.72(m, 1H), 2.79-2.82(m,1H), 2.90-2.96(m, 1H), 3.25-
3
4
(a) I. T. Raheem, P. S. Thiara, and E. N. Jacobsen, Org. Lett.
2008, 10, 1577; (b) M. J. Wanner, R. N. S. van der Haas, J. H.
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Claveau, M. J. Wanner, S. Ingemann, J. H. Maarseveen, H.
3.29(m, 1H), 3.40(d, J=13.8Hz, 1H), 3.89(s, 3H), 3.92(d,
J=13.8Hz, 1H), 4.68(s, 1H), 6.80-6.82(m, 1H), 7.02-7.03(m, 1H),
7.09(d, J=9.0Hz, 1H), 7.19(b, 1H), 7.28-7.30(m, 1H), 7.35-
7.37(m, 3H), 7.39-7.41(m, 4H).13C NMR (150 MHz, CDCl3) δ
154.04, 141.38, 139.47, 135.77, 131.43, 129.03, 128.77,
128.25, 128.09, 127.59, 126.96, 64.65, 58.31, 56.01, 48.33,
21.21. IR: 705.25, 738.68, 895.96, 1265.31, 1421.76, 1634.69,
2305.33, 2987.16, 3054.50, 3449.53.
Hiemstra, Chem. Commun. 2012
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Chrzanowska, A. Grajewska, M. D. Rozwadowska, Chem. Rev.
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Conflicts of interest
The authors declare no competing financial interest.
10 Q. F. Wu, C. Zheng, C. X. Zhou, S. L. You, Chem. Sci. 2016, 7,
4453.
11 Y. H. Wang, L. Y. Cui, Y. M. Wang, Z. H. Zhou, Tetrahedron-
Asymmetry. 2016, 27, 85.
Acknowledgements
12 S. Ahmad, L. Shukla, J. Szawkało, P. Roszkowski, J. K. Maurin,
Z. Czarnocki, Catal. Commun. 2017, 89, 44.
13 L. Evanno, J. Ormala, P. M. Pihko, Chem, Eur, J. 2009, 75,
12963.
We thank the Professor Hujun Xie in Zhejiang Gong Shang
University for the theoretical calculation. We also thank the
National Natural Science Foundation of China (21676253) for
financial support.
14 (a) L. M. Overvoorde, M. N. Grayson, Y. Luo, J. M. Goodman,
́
J. Org. Chem. 2015, 80, 2634; (b) M. Frias, R. Mas-Balleste, S.
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DOI: 10.1002/adsc.201700986.
Notes and references
1
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2030;(b) G. Tatsui, J. Pharm. Soc. Jpn. 1928, 48, 92.
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