Organocatalytic enantioselective pictet-spengler reactions for the syntheses of 1-substituted 1,2,3,4-tetrahydroisoquinolines

Article abstract of DOI:10.1021/jo501099h

A series of 1-substituted 1,2,3,4-tetrahydroisoquinolines was prepared from N-(o-nitrophenylsulfenyl)phenylethylamines through BINOL-phosphoric acid [(R)-TRIP]-catalyzed asymmetric Pictet-Spengler reactions. The sulfenamide moiety is crucial for the rate

Full text of DOI:10.1021/jo501099h

Article
pubs.acs.org/joc
Organocatalytic Enantioselective Pictet−Spengler Reactions for the
Syntheses of 1‑Substituted 1,2,3,4-Tetrahydroisoquinolines
Elma Mons, Martin J. Wanner, Steen Ingemann, Jan H. van Maarseveen, and Henk Hiemstra*
Van’t Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands
S
* Supporting Information
ABSTRACT: A series of 1-substituted 1,2,3,4-tetrahydroisoquinolines was prepared from N-(o-nitrophenylsulfenyl)-
phenylethylamines through BINOL-phosphoric acid [(R)-TRIP]-catalyzed asymmetric Pictet−Spengler reactions. The
sulfenamide moiety is crucial for the rate and enantioselectivity of the iminium ion cyclization and the products are readily
recrystallized to high enantiomeric purity. Using this methodology we synthesized the natural products (R)-crispine A, (R)-
calycotomine and (R)-colchietine, the synthetic drug (R)-almorexant and the (S)-enantiomer of a biologically active (R)-AMPA-
antagonist.
dopamine in aqueous solutions.5 Norcoclaurine synthase
INTRODUCTION
■
(NCS) was identified as a Pictet−Spenglerase that catalyzes
Natural and synthetic 1-substituted tetrahydroisoquinolines
(e.g., norcoclaurine, emetine and solifenacin) and their more
the enantioselective condensation of dopamine with p-
hydroxyphenylacetaldehyde.6a Optimization of this biocatalytic
complicated biosynthetic derivatives such as morphine (Figure
reaction produced (S)-norcoclaurine on gram scale,6b and the
1) have received broad attention in medicinal and synthetic
chemistry.1,2 The diverse pharmaceutical applications of
scope was extended to several benzyl-substituted tetrahydroi-
soquinolines.6c,d
alkaloids of this class have stimulated the development of
An increasing number of enantioselective Pictet−Spengler
reactions mediated by organocatalysts such as BINOL- and
SPINOL-phosphoric acids and functionalized thioureas are
reported in the literature, although the amine precursors have
been restricted to tryptamines and derivatives thereof.7 The
highly nucleophilic indole system in combination with the
hydrogen bonding properties of the indole N−H make this
aromatic ring system an ideal reaction partner in many
organocatalytic conversions. The phenylethylamine counter-
part, required for tetrahydroisoquinoline synthesis, has no clear
examples in the enantioselective Pictet−Spengler condensation
yet. One closely related example is a ruthenium-catalyzed
isomerization combined with an enantioselective organo-
catalyzed Pictet−Spengler type cyclization reaction described
by Toda and Terada.8
several synthetic methods, of which catalytic approaches are
obviously most attractive. Transition metal-catalyzed asym-
metric hydrogenation reactions of isoquinolines and their 3,4-
dihydro analogues with, e.g., iridium, rhodium and ruthenium
catalysts are frequently used and often provide high ee values
with an expanding number of substrates (Scheme 1).3
However, metal-free catalytic approaches may be more
desirable in view of the pharmaceutical applications. The
most direct approach would be the biomimetic Pictet−Spengler
condensation reaction starting from a suitably functionalized
phenylethylamine such as dopamine and a range of aldehydes
(Scheme 1).2
Recently, several remarkable publications described racemic
Pictet−Spengler syntheses of tetrahydroisoquinolines. Stambuli
and co-workers reported the use of calcium hexafluoroisoprop-
oxide as a very effective catalyst for condensation of 3-
hydroxyphenylethylamines, not only with aldehydes but also
with unactivated ketones.4 Inorganic phosphates played an
essential role in a tetrahydroisoquinoline synthesis directly from
Received: May 19, 2014
Published: July 21, 2014
© 2014 American Chemical Society
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Figure 1. Pharmaceutically relevant 1-substituted tetrahydroisoquinolines.
Scheme 1. Catalytic Synthetic Approaches to 1-Substituted Tetrahydroisoquinolines
Scheme 2. Preparation of N-Substituted Phenylethylamines
a
Table 1. Influence of the N-Substituent on the Pictet−Spengler Cyclization
b
c
entry
R
product, yield (%)
T (°C), time
ortho/para
ee para (%)
1
2
3
4
H (2)
7a/8a, 79
7b/8b, 94
7c/8c, 74
7d/8d, 84
110, 48 h
rt, 36 h
rt, 36 h
90, 48 h
52/48
15/85
30/70
<5/95
0
methyl (5)
benzyl (6)
4
29
49
d
Nps (3)
a
Reaction conditions: amine (0.02 mmol), p-bromobenzaldehyde (0.03 mmol), (R)-TRIP (5 mol %, see Table 2 for its structure), toluene (0.2 mL).
Determined by H NMR. Determined by HPLC. Nps = o-nitrophenylsulfenyl.
b
c
d
1
In this account we will describe successful enantioselective
position for ring closure to occur. A 3-hydroxy substituent as
Pictet−Spengler condensations to interesting 1-substituted
tetrahydroisoquinolines catalyzed by enantiopure biarylphos-
phoric acids. Key issues to attain success are the substitution
pattern of the aromatic ring in the phenylethylamine starting
material and the ancillary substituent on nitrogen.
in 2 (Scheme 2) makes the aromatic ring considerably more
reactive, while the methyl on O-4 protects the catechol part of
dopamine against air oxidation.4,8 Furthermore, it was clear
from our tryptamine research and other work that the presence
of an appropriate N-substituent is crucial for the formation of
an iminium intermediate with suitable reactivity.7d−f
Our synthetic efforts started with the preparation of the
amines for the Pictet−Spengler reactions. Thus, β-(3-
benzyloxy-4-methoxyphenyl)ethylamine (1) was prepared
from isovanillin in three steps (Scheme 2) according to a
literature procedure.9 Hydrogenolysis of the benzyl ether
RESULTS AND DISCUSSION
■
Previous studies in our group on Pictet−Spengler reactions
with BINOL-phosphoric acids as catalyst have shown that the
electron-donating 3-methoxy substituent in, e.g., 3,4-dimethox-
yphenylethylamine is not sufficiently activating the para-
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a
Table 2. Optimization of the Reaction Conditions with 3
entry
cocatalyst
additive
T (°C)
conv (%)
ee (%)
1
2
3
4
5
6
7
−
−
−
−
105
105
105
105
105
105
90
40 (3 h)
40 (3 h)
70 (3 h)
50 (3 h)
40 (3 h)
90 (3 h)
100 (18 h)
49
62
70
48
44
72
73
(R)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
3 Å MS
4 Å MS
b
argon
c
argon
a
Reaction conditions: Nps-amine 3 (0.02 mmol), p-bromobenzaldehyde (0.03 mmol), (R)-TRIP (5 mol %), BINOL (20 mol %), toluene (0.2 mL).
Slow argon flow to remove water. 10 mol % (R)-TRIP. Nps = o-nitrophenylsulfenyl.
b
c
produced primary amine 2, which was converted into o-
nitrophenylsulfenamide 3 and N-(benzyl)phenylethylamine 6
in single steps. N-Methyl derivative 5 was prepared from 1 via
N-nosylation followed by alkylative methylation to give 4 and
subsequent hydrogenolytic debenzylation.
In the event (Table 1, entry 4) Nps-amine 3 cyclized in good
yield at 90 °C. This temperature is probably required to
generate the N-sulfenyliminium ion. A first screening with 3
and p-bromobenzaldehyde showed that (R)-3,3′-bis(2,4,6-
triisopropylphenyl)-BINOL-phosphoric acid [(R)-TRIP] was
the optimal catalyst. In all reactions the amount of the “ortho”-
cyclization product was reduced to less than 5%. Further
optimization of the ee was accomplished by using (S)-BINOL
as a cocatalyst (Table 2). Water formed during the reaction
might have a negative effect on the reaction, but addition of
drying agents such as molecular sieves or sodium sulfate to the
reaction mixture had a negative effect on both the conversion
and the ee. Reproducible results could be obtained by passing a
slow argon flow over the solution at 90 °C, thereby
azeotropically removing water that is formed during the
condensation.
Next the scope in the aldehyde was examined. A series of
aromatic aldehydes revealed that substituent have a strong
influence on the ee (Table 3). Benzaldehydes with an electron-
withdrawing substituent at the para-position gave good ee’s
(entries 4, 5, 7, 9), while benzaldehyde itself and its p-methoxy
analogue gave considerably lower values (entries 1 and 6). This
could be a result of a more intimate ion pair in the ring closing
transition state derived from electron-deficient aldehydes,
inducing a stronger interaction with the (R)-TRIP counterion.
Apparently, meta- and ortho-substituents fit less well in the
transition state with (R)-TRIP and require further catalyst
optimization (entries 2, 3, 8, 10, 11).
The primary amine 2 quickly formed the corresponding
imine when heated with p-bromobenzaldehyde under BINOL-
phosphoric acid catalysis in toluene (Table 1, entry 1).
However, subsequent Pictet−Spengler cyclization was rather
slow to provide a remarkable 1:1 mixture of ortho/para
regioisomers without any enantioselectivity. On the other hand
the secondary N-methyl and N-benzyl amines 5 and 6 showed
good Pictet−Spengler condensation already at room temper-
ature (Table 1, entries 2 and 3). Moderate ortho/para
regioselectivity was observed, with low ee for the desired
para-isomer. Apparently, iminium ion formation between the
secondary amine and an aldehyde occurred readily, requiring
only a weakly acidic catalyst such as, e.g., a phenolic OH. To
increase the contribution of the BINOL-phosphoric acid
catalyst to iminium ion formation, the substituent on nitrogen
had to become more electron-withdrawing. Terada et al. have
shown that N-Boc and N-phosphinyl substituted phenylethyl-
amines prevent formation of the iminium ion with aldehydes
and only marginal Pictet−Spengler reaction occurred.8
We then turned our attention to sulfenyl substituents on
nitrogen, which have electron-withdrawing properties in
between N-alkyl and N-carbonyl substituents. The tritylsulfenyl
(Ph3CS) substituent, a nitrogen protecting group that
previously showed good results in the synthesis of β-carbolines
from tryptamines, was not stable enough under the required
Pictet−Spengler conditions.10 It eventually appeared that the
ortho-nitrophenylsulfenyl substituent (Nps, see 3) was the
group of choice. o-Nitrophenyl-sulfenamides have excellent
properties with respect to stability and crystallinity (bright
yellow colored), although their NMR spectra often suffer from
broad signals due to hindered rotation about the NS-bond.11
The Nps group has been used as an N-protecting group in, e.g.,
peptide chemistry and as an activating group in Friedel−Craft
reactions.12 The Nps-group was readily introduced by use of
commercially available o-nitrophenylsulfenyl chloride. Removal
of this protecting/activating Nps-group is known to occur in
high yield through treatment with dilute hydrochloric acid.
The enantiomeric purity of a number of Pictet−Spengler
products could be readily increased by making use of the
crystallization properties of the Nps-substituent. Both the p-Cl
and p-Br derivatives 9d and 8d completely crystallized as
racemates from dichloromethane/petroleum ether solutions,
leaving the virtually pure (S)-enantiomer in the filtrate. To
prove its absolute configuration the former p-chlorophenyl-
20
tetrahydroisoquinoline (9d) was converted to 11 ([α]D
=
+224) in three simple steps (Scheme 3). This confirmed the
20
(S)-configuration of 11, as the (R)-enantiomer of 11 ([α]D
=
−206, 98% ee) is well-known as an AMPA receptor
antagonist.3c
Aliphatic aldehydes appeared to be more reactive in the
Pictet−Spengler condensation than the aromatic aldehydes so
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a
removal of the sulfenate byproduct gave a much lower yield of
the lactam and a considerable amount of oxidation to an
isoquinoline. Subsequent O-methylation of purified 17 afforded
18 and removal of the carbonyl through treatment with LiAlH4
then gave crispine A (19) as shown in Scheme 4.
Table 3. Pictet−Spengler with Aromatic Aldehydes
For the synthesis of calycotomine (21)14 a suitably protected
2-hydroxyacetaldehyde was required as the starting material.
After comparing several protecting groups such as benzyl,
TBDMS and pivaloyl, acetoxyacetaldehyde was selected as the
most convenient with respect to deprotection and crystal-
lization properties (Table 4, entry 5 and Scheme 5). The
Pictet−Spengler product (58% ee) was O-methylated before
the acetyl group was removed from the primary alcohol. The
racemic 20 was allowed to crystallize, which left the virtually
enantiopure product in the mother liquor. The sulfenamide
NS-bond in 20 was then cleaved in the presence of thiophenol
(in order to prevent partial intramolecular sulfenylation of the
primary alcohol) providing the alkaloid calycotomine as a
crystalline product.
yield
ee refined
b
c
entry
ArCHO
PhCHO
product
(%)
ee (%)
(%)
1
2
3
4
5
6
7
8
9
10
9a
9b
9c
9d
8d
9e
9f
75
83
75
83
79
62
79
85
51
79
26
−
−
−
99
99
−
−
_
2-ClC6H4CHO
3-ClC6H4CHO
4-ClC6H4CHO
4-BrC6H4CHO
4-MeOC6H4CHO
4-CF3C6H4CHO
3-NO2C6H4CHO
4-NO2C6H4CHO
0
47
71 (S)
73 (S)
0
86 (S)
28
9g
9h
9i
68
−
3,4-
24
(MeO)2C6H4CHO
(R)-(+)-Colchietine (22) was prepared in two steps by
deprotection and N-demethylation of p-methoxyphenylethyl-
tetrahydroisoquinoline (14, Scheme 6). This alkaloid was
isolated from Colchicum szovitsii and its (S)-(+) configuration
was assigned on the basis of comparison with other alkaloids.15
In chloroform we measured a specific rotation of +8, but in
methanol as a solvent we observed no significant rotation,
although the literature reports a value of +8 in this solvent. A
recent synthetic publication on the (S)-enantiomer of
colchietine by Uenishi et al. describes a rotation of +1.9 in
methanol (87% ee), which demonstrates the fluctuation of
these values.16 Better proof of the configuration was obtained
by conversion of 14 into trimethoxytetrahydroisoquinoline 23,
of which the (R)-configuration has been confirmed by
degradation studies.17 Further support was inferred from
HPLC-analysis, as on an AD-Chiralpak or ODH-Chiralcel
column all of the tetrahydroisoquinoline (S)-enantiomers
eluted before the (R)-enantiomers.18,19 In agreement with
these results, 15 was converted into almorexant precursor 24,
the (R)-(+)-enantiomer of the bioactive (S)-compound
(Scheme 7).20
11
2-naphthylCHO
9j
80
64
−
a
Reaction conditions: Nps-amine 3 (0.2 mmol), aldehyde (0.3 mmol),
(R)-TRIP (10 mol %), (S)-BINOL (20 mol %), toluene, 90 °C, slow
argon flow, 18 h. Isolated yield. Nps = o-nitrophenylsulfenyl. ee of
the product in the filtrate after removal of the crystalline racemate.
b
c
that the reactions were conducted at a somewhat lower
temperature of 80 °C with 5 mol % catalyst (Table 4). n-
Hexanal was selected for optimization studies. Small improve-
ments were obtained by using (S)-BINOL and acetic acid as
cocatalysts. Again the use of molecular sieves as drying agents
had a negative effect on both the yield and the ee.
Acetoxyacetaldehyde (Tabel 4, entry 5) was so reactive that
the reaction could be carried out at room temperature, but this
did not result in a higher ee. The product 16 had the opposite
configuration as the major enantiomer in comparison with the
products 12−15 (note that all compounds are designated R
because of a change in substituent priorities). The products
from the four functionalized aldehydes (Table 4, entries 2−5)
could be obtained in high enantiomeric purity via recrystalliza-
tion and were then further converted into alkaloids and
bioactive compounds (Schemes 4−7).
tert-Butyl 4-oxobutanoate (Table 4, entry 2) appeared to be a
much more suitable precursor than the corresponding methyl
ester for the synthesis of the popular target alkaloid crispine A
(19),13 both in terms of enantioselectivity and crystallization
properties. The Pictet−Spengler product 13 (99% ee, after
removal of the crystalline racemate) was first treated with dry
HCl in ethanol (generated from acetyl chloride). The resulting
mixture of the secondary amine and the ethyl sulfenate
byproduct was heated in refluxing xylene to produce lactam 17.
The presence of the ethyl sulfenate byproduct in this cyclization
process seemed to have some beneficial effect, as earlier
CONCLUSION
■
To achieve enantioselective Pictet−Spengler condensation of
phenylethylamines to 1-substituted 1,2,3,4-tetrahydroisoquino-
lines, we introduced a moderately strong electron-withdrawing
substituent on the nitrogen atom. The Nps (o-nitrophenylsul-
fenyl) substituent demonstrated excellent properties with
respect to reactivity and stability. Recrystallization of the
Pictet−Spengler products was strongly facilitated by the Nps-
group and gave tetrahydroisoquinolines with high enantiopur-
ity. In addition, the Nps substituent displayed protecting group
properties that were required for the synthetic transformations
Scheme 3. Synthesis of an AMPA Receptor Antagonist
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a
Table 4. Pictet−Spengler with Aliphatic Aldehydes
b
c
entry
RCHO
n-C5H11CHO
product
yield (%)
ee (%)
ee refined (%)
1
2
3
4
5
12
13
14
15
16
88
88
84
75
70 (R)
67 (R)
72 (R)
33 (R)
58 (R)
−
t-BuO2CCH2CH2CHO
p-MeOC6H4CH2CH2CHO
p-F3CC6H4CH2CH2CHO
AcOCH2CHO
99
99
95
97
d
92
a
Reaction conditions: Nps-amine 3 (0.2 mmol), aldehyde (0.3 mmol), (R)-TRIP (5 mol %), (S)-BINOL (20 mol %), HOAc (20−50 mol %),
b
c
toluene, 80 °C, 18 h. Isolated yield. ee of the product in the filtrate after removal of the crystalline racemate, except for entry 3, in which case the
virtually pure enantiomer crystallized. Slow addition of the aldehyde; reaction at rt.
d
Scheme 4. Synthesis of (R)-Crispine A
Scheme 7. Synthesis of an (R)-Almorexant Precursor
toward a series of biologically relevant alkaloids and bioactive
compounds.
Scheme 5. Synthesis of (R)-Calycotomine
EXPERIMENTAL SECTION
■
General Information. All 1H NMR and 13C NMR spectra (APT)
were recorded (1H 400 MHz, 13C 100 MHz) at room temperature in
CDCl3. Accurate mass measurements were performed with electro-
spray ionization (ESI). All reactions were carried out in oven-dried
glassware with magnetic stirring under a nitrogen atmosphere. THF
was freshly distilled from sodium and benzophenone. Toluene was
distilled over calcium hydride and stored on 4 Å molecular sieves.
Aldehydes were purified by recrystallization, distillation or chromatog-
raphy on silica gel. (R)-3,3′-Bis(2,4,6-triisopropylphenyl)-BINOL-
phosphoric acid [(R)-TRIP] was prepared according to a literature
method.21 All Nps-protected tetrahydroisoquinolines were bright
1
yellow, stable compounds. The H and 13C NMR spectra, however,
showed extreme line broadening for atoms in the vicinity of the
Scheme 6. Synthesis of (R)-Colchietine and the Isomer 23
nitrogen−sulfur bond.11b
β-(3-Hydroxy-4-methoxyphenyl)ethylamine (2). A solution of
β-(3-benzyloxy-4-methoxyphenyl)ethylamine 19 (9.00 g, 35.0 mmol)
in methanol (200 mL) was stirred with 10% Pd/C (0.9 g) under a
balloon of hydrogen gas for 18 h at rt. After filtration of the catalyst
and removal of the solvent compound 2 (5.85 g, 35.0 mmol, 100%)
was obtained as a solid: mp 139−150 °C; IR (film) ν 3337, 3275,
1
2932, 1511 cm−1; H NMR (400 MHz, DMSO-d6) δ 6.79 (d, J = 8.2
Hz, 1 H), 6.62 (d, J = 1.9 Hz, 1 H), 6.54 (dd, J = 8.2, 1.9 Hz, 1 H), 4.0
(broad, NH, OH, H20), 3.71 (s, 3 H), 2.69 (m, 2 H), 2.49 (m, 2 H);
13C NMR (101 MHz, DMSO-d6) δ 146.8, 146.2, 133.1, 119.2, 116.3,
112.5, 55.9, 39.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C9H14NO2 168.1025, found 168.1016.
N-(2-Nitrophenylsulfenyl)-β-(3-hydroxy-4-methoxyphenyl)-
ethylamine (3). Amine 2 (1.67 gr, 10.0 mmol) was dissolved in a
mixture of CHCl3 (100 mL), methanol (5 mL) and triethylamine (0.5
mL) in a 250 mL flask with stirring and heating until fully dissolved.
The solution was cooled to 0 °C, 100 mL saturated K2CO3 solution in
water was added, and after stirring for 5 min 2-nitrophenylsulfenyl
chloride (2.28 gr, 12.0 mmol) was added in three portions. After
vigorous stirring for 1 h TLC analysis [silica gel, ethyl acetate/
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methanol/25% NH4OH (v/v/v = 90/8/2) as eluent] confirmed full
conversion. Extractive workup with CHCl3, drying over MgSO4 and
removal of the solvents gave a crude mixture from which some solid
Nps-dimer was removed by trituration with an ethyl acetate/
petroleum ether mixture. The product was obtained in pure form by
flash chromatography [silica gel, dichloromethane/petroleum ether/
ethyl acetate (v/v/v = 50/50/2−50/50/6) as eluent]. Crystallization
occurred after complete removal of residual ethyl acetate by
coevaporation twice with dichloromethane. Dissolving the product
in dichloromethane, addition of petroleum ether and cooling in ice
gave 3 as yellow crystals (2.09 gr, 6.5 mmol, 65%): mp 77−78 °C; IR
(film) ν 3488, 3350, 2935, 1508 cm−1; 1H NMR (400 MHz, CDCl3) δ
8.28 (dd, J = 8.3, 2.0 Hz, 1 H), 7.81 (dd, J = 8.3, 1.2 Hz, 1 H), 7.59 (m,
1 H), 7.25 (m, 1 H), 6.85−6.82 (m, 2 H), 6.75 (m, 1 H), 5.63 (s, 1 H),
3.91 (s, 3 H), 3.22 (m, 2 H), 2.85 (m, 2 H), 2.72 (t, J = 5.7 Hz, NH);
13C NMR (101 MHz, CDCl3) δ 145.6, 145.4, 145.1, 142.3, 133.5,
131.8, 125.5, 124.3, 124.1, 120.2, 114.8, 110.7, 55.8, 52.4, 36.0; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C15H17N2O4S, 321.0909, found,
321.0895. Anal. Calcd for C15H16N2O4S: C, 56.24; H, 5.03; N, 8.74.
Found: C, 56.22; H, 5.18; N, 8.68.
34.8; HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H20NO2,
258.1494, found, 258.1506.
1-(4-Bromophenyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahy-
droisoquinoline (7a) and 1-(4-Bromophenyl)-7-methoxy-8-
hydroxy-1,2,3,4-tetrahydroisoquinoline (8a). A solution of β-
(3-hydroxy-4-methoxyphenyl)ethylamine 2 (68.4 mg, 0.40 mmol), 4-
bromobenzaldehyde (82.5 mg, 0.50 mmol) and (R)-TRIP (15.0 mg, 5
mol %) in toluene (4 mL) was heated at 110 °C under a slow argon
flow to remove water. After 30 min the vessel was stoppered, and
heating was continued for 48 h. Chromatographic separation [silica
gel, ethyl acetate/methanol/25% NH4OH (v/v = 94/4/2) as eluent]
gave 7a as a glass (ortho isomer, 54.5 mg, 0.163 mmol, 41%) with 24%
ee [Chiralcel OD-H, n-heptane/i-propanol (v/v = 70/30) as eluent,
0.5 mL/min, t (minor) = 22.37 min, t (major) = 26.26 min]; IR (film)
1
ν 2932, 1493 cm−1; H NMR (400 MHz, CDCl3) δ 7.41 (m, 2 H),
7.07 (m, 2 H), 6.81 (d, J = 8.3 Hz, 1 H), 6.72 (d, J = 8.3 Hz, 1 H), 5.30
(s, 1 H), 3.85 (s, 3 H), 2.70−2.95 (m, 4 H); 13C NMR (101 MHz,
CDCl3) δ 144.3, 143.3, 142.2, 131.1, 129.9, 128.9, 123.1, 120.6, 119.7,
109.6, 56.0, 54.8, 38.4, 28.6; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C16H17BrNO2, 334.0443, found, 334.0431.
N-Methyl-β-(3-benzyloxy-4-methoxyphenyl)ethylamine (4).
4-Nitrophenylsulfonyl chloride (6.65 g, 30.0 mmol) was added in three
portions to a solution of β-(3-benzyloxy-4-methoxyphenyl)ethylamine
19 (6.17 g, 24.0 mmol) and triethylamine (5.7 mL, 40 mmol) in
anhydrous CH2Cl2 (120 mL) at 0 °C. The ice bath was removed, and
after stirring for 2 h water (100 mL) was added. Extractive workup and
flash chromatography [silica gel, petroleum ether/ethyl acetate (v/v =
75/25−40/60) as eluent] yielded crude N-4-nitrophenylsulfonyl-β-(3-
benzyloxy-4-methoxyphenyl)ethylamine (8.85 g, 20.0 mmol, as a glass,
which was immediately dissolved in anhydrous DMSO (75 mL) and
stirred with K2CO3 (13.8 g, 100 mmol) and iodomethane (1.56 mL,
25.0 mmol) for 90 min at rt. Thiophenol (5.65 mL, 55 mmol) was
added, and stirring was continued for 4 h. Extractive workup with ethyl
acetate and chromatographic purification [silica gel, petroleum ether/
ethyl acetate (v/v = 75/25−0/100) and ethyl acetate/methanol/
triethylamine (v/v/v = 93/5/2) as eluent] gave 4 (3.03 g, 11.2 mmol,
8a: glass, para isomer, 50.5 mg, 0.151 mmol, 38%, with 0% ee
[Chiralcel OD-H, n-heptane/i-propanol (v/v = 70/30) as eluent, 0.5
mL/min, t = 16.70 min, t = 22.44 min); IR (film) ν 2920, 1511 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.50 (m, 2 H), 7.20) d, 2 H), 6.71 (s, 1
H), 6.23 (s, 1 H), 5.06 (s, 1 H), 3.71 (s, 3 H), 3.25 (m, 1 H), 3.10 (m,
1 H), 2.96 (m, 1 H), 2.75 (m, 1 H); 13C NMR (101 MHz, CDCl3) δ
145.0, 144.4, 144.0, 131.5, 130.7, 128.5, 128.4, 121.2, 114.6, 110.1,
99.9, 60.8, 55.9, 41.7, 28.9; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C16H17BrNO2, 334.0443, found, 334.0439.
N-Methyl-1-(4-bromophenyl)-6-hydroxy-7-methoxy-1,2,3,4-
tetrahydroisoquinoline (7b) and N-Methyl-1-(4-bromophen-
yl)-7-methoxy-8-hydroxy-1,2,3,4-tetrahydroisoquinoline (8b).
A solution of N-methyl-β-(3-hydroxy-4-methoxyphenyl)ethylamine 5
(72.4 mg, 0.40 mmol), 4-bromobenzaldehyde (82.5 mg, 0.50 mmol)
and (R)-TRIP (15.0 mg, 5 mol %) in toluene (4 mL) was stirred at rt
for 36 h. Chromatography [silica gel, ethyl acetate/petroleum ether
(v/v = 20/80−50/50) as eluent] gave 7b as a glass (ortho isomer, 23.4
mg, 0.068 mmol, 17%) with 24% ee [Chiralcel OD-H, n-heptane/i-
propanol (v/v = 70/30) as eluent, 0.5 mL/min, t (minor) = 10.49 min,
t (major) = 18.77 min]; 1H NMR (400 MHz, CDCl3, selected signals
taken from an ortho/para mixture) δ 6.77 (d, J = 8.3 Hz, 1 H, 6.71 (d, J
= 8.3 Hz, 1 H), 4.84 (bs, 1 H), 3.77 (s, 3 H), 2.37 (s, 3 H). 8b (glass,
para isomer, 106.8 mg, 0.307 mmol, 77%) with 7% ee [Chiralcel OD-
H, n-heptane/i-propanol (v/v = 70/30) as eluent, 0.5 mL/min, t
(minor) = 8.93 min, t (major) = 12.19 min]; IR (film) ν 2948, 2786,
1512 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.46 (m, 2 H), 7.17 (m, 2
H), 6.66 (s, 1 H), 6.05 (s, 1 H), 4.20 (m, 1 H), 3.60 (s, 3 H), 3.06−
3.15 (m, 2 H), 2.55−2.75 (m, 2 H), 2.23 (s, 3 H); 13C NMR (101
MHz, CDCl3) δ 145.0, 144.1, 131.3, 130.6, 127.1, 121.0, 119.0, 113.9,
110.4, 70.2, 55.8, 51.8, 44.0, 28.3; HRMS (ESI-TOF) m/z [M + H]+
calcd for C17H19BrNO2, 348.0599, found, 348.0600.
1
56%) as a syrup: IR (film) ν 2932, 1514 cm−1; H NMR (400 MHz,
CDCl3) δ 7.45 (m, 2 H), 7.38 (m, 2 H), 7.33 (m, 1 H), 6.85 (m, 1 H),
6.77 (m, 2 H), 5.17 (s, 2 H), 3.89 (s, 3 H), 2.77 (m, 2 H), 2.72 (m, 2
H), 2.40 (m, 3 H); 13C NMR (101 MHz, CDCl3) δ 148.0, 147.8,
137.0, 132.4, 128.3, 127.6, 127.2, 121.1, 114.7, 111.8, 70.8, 55.9, 53.1,
36.2, 35.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C17H22NO2,
272.1651, found, 272.1658.
N-Methyl-β-(3-hydroxy-4-methoxyphenyl)ethylamine (5). A
solution of 4 (0.50 g, 1.84 mmol) in methanol (20 mL) was stirred
with 10% Pd/C (0.15 g) under a balloon of hydrogen gas for 16 h at
rt. After filtration of the catalyst and removal of the solvent compound
5 (0.33 g, 1.82 mmol, 99%) was obtained as a glass: IR (film) ν 2500−
1
3200 (broad), 1501 cm−1; H NMR (400 MHz, CDCl3) δ 6.75 (d, 1
H, J = 8.2 Hz, 6.68, (d, 1 H, J = 2.0 Hz), 6.61 (dd, 1 H, J = 8.2, 2.0
Hz), 5.42 (broad, 2 H, OH, NH), 3.81 (s, 3 H), 2.83 (m, 2 H), 2.71
(m, 2 H), 2.40 (s, 3 H); 13C NMR (101 MHz, CDCl3) δ 146.7, 146.1,
132.0, 118.8, 115.8, 111.3, 55.6, 52.4, 35.4, 34.4; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C10H16NO2, 182.1181, found, 182.1178.
N-Benzyl-β-(3-hydroxy-4-methoxyphenyl)ethylamine 6. A
solution of β-(3-hydroxy-4-methoxyphenyl)ethylamine 2 (0.816 g,
4.0 mmol) and benzaldehyde (0.45 mL, 4.4 mmol) in methanol (50
mL) was stirred at rt for 18 h. After cooling in an ice bath sodium
borohydride (0.228 g, 6.0 mmol) was added in three portions, and
stirring was continued at rt for 1 h. Most of the methanol was removed
by evaporation, and the residue was quenched with dilute aqueous
sodium carbonate and extracted with ethyl acetate. Flash chromatog-
raphy [silica gel, ethyl acetate and ethyl acetate/methanol/triethyl-
amine (v/v/v = 92/5/3) as eluent] and recrystallization from ethyl
acetate/petroleum ether gave 6 (0.903 g, 3.51 mmol, 78%) as needles:
N-Benzyl-1-(4-bromophenyl)-6-hydroxy-7-methoxy-1,2,3,4-
tetrahydroisoquinoline (7c) and N-Benzyl-1-(4-bromophenyl)-
7-methoxy-8-hydroxy-1,2,3,4-tetrahydroisoquinoline (8c). A
solution of N-benzyl-β-(3-hydroxy-4-methoxyphenyl)ethylamine 1c
(102.8 mg, 0.40 mmol), 4-bromobenzaldehyde (82.5 mg, 0.50 mmol)
and (R)-TRIP (15.0 mg, 5 mol %) in toluene (4 mL) was stirred at rt
for 36 h. Chromatography with ethyl acetate/petroleum ether mixtures
gave 7c as a glass (ortho isomer, 37.8 mg, 0.089 mmol, 22%) with 24%
ee [Chiralcel OD-H, n-heptane/i-propanol (v/v = 70/30) as eluent,
0.5 mL/min, t (minor) = 10.49 min, t (major) = 18.77 min]; IR (film)
1
ν 3524, 2926, 1493, cm−1; H NMR (400 MHz, CDCl3) δ 7.25−7.42
(m, 7 H), 7.10 (m, 2 H), 6.82 (d, J = 8.3 Hz, 1 H), 6.74 (d, J = 8.3 Hz,
1 H), 5.52 (s, 1 H), 5.02 (s, 1 H), 3.87 (s, 3 H), 3.73 (d, J = 13.4 Hz, 1
H), 3.65 (d, J = 13.4 Hz, 1 H), 2.9−3.05 (m, 2 H), 2.65−2.75 (m, 2
H); 13C NMR (101 MHz, CDCl3) δ 144.1, 142.6, 141.4, 139.4, 131.1,
130.6, 128.9, 128.4, 128.2, 127.0, 122.8, 120.5, 119.4, 109.4, 59.9, 57.7,
56.0, 43.1, 25.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C23H23BrNO2, 424.0912, found, 424.0930.
1
mp 87−88.5 °C; IR (film) ν 2934, 1510 cm−1; H NMR (400 MHz,
CDCl3) δ 7.26−7.35 (m, 5 H), 6.79 (d, J = 8.2, 1 H), 6.76 (m, 1 H),
6.68 (dd, J = 8.2, 2.0 Hz, 1 H), 3.88 (s, 3 H), 3.82 (s, 2 H), 2.90 (m, 2
H), 2.76 (m, 2 H); 13C NMR (101 MHz, CDCl3) δ 146.1, 145.7,
139.2, 132.3, 128.3, 128.1, 126.9, 119.3, 115.5, 111.0, 55.7, 53.4, 49.9,
7385
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Article
8c: glass, para isomer, 88.2 mg, 0.208 mmol, 52%, with 29% ee
[Chiralcel OD-H, n-heptane/i-propanol (v/v = 70/30) as eluent, 0.5
mL/min, t (minor) = 9.94 min, t (major) = 11.33 min]; IR (film) ν
CDCl3) δ 8.25 (dd, J = 8.3, 1.2 Hz, 1 H), 7.97 (broad d, J = 8.3 Hz, 1
H), 7.55 (ddd, J = 8.3, 7.1, 1.4 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H),
7.25−7.14 (m, 2 H), 7.11 (t, J = 7.2 Hz, 1 H), 6.93 (broad s, 1 H),
6.78 (s, 1 H), 6.26 (s, 1 H), 5.77 (broad s, 1 H), 5.57 (s, 1 H), 3.71 (s,
3 H), 3.43 (broad, 1 H), 3.19 (broad, 1 H), 3.07 (broad, 1 H), 2.86
(broad, 1 H); 13C NMR (101 MHz, CDCl3) δ 145.3, 144.7, 141.8,
140.7, 135.4, 133.5, 130.9, 129.6, 128.7, 127.6, 126.4, 125.6, 125.4,
124.5, 114.2, 110.0, 65.7, 55.9, 47.7, 26.1; HRMS (ESI-TOF) m/z [M
+ H]+ calcd for C22H20ClN2O4S, 443.0832, found, 443.0833.
1
3524, 2931, 1511, cm−1; H NMR (400 MHz, CDCl3) δ 7.46 (m, 2
H), 7.24−7.35 (m, 7 H), 6.70 (s, 1 H), 6.17 (s, 1 H), 5.53 (br, 1 H,
OH), 4.54 (m, 1 H), 3.79 (d, J = 13.6 Hz, 1 H), 3.67 (s, 3 H), 3.32 (d,
J = 13.6 Hz, 1 H), 3.05 (m, 1 H), 2.94 (m, 1 H), 2.70 (m, 1 H), 2.53
(m, 1 H); 13C NMR (101 MHz, CDCl3) δ 144.8, 144.0, 143.7, 139.2,
131.3, 131.2, 131.1, 130.6, 128.9, 128.6, 128.2, 127.8, 126.9, 120.9,
113.9, 110.7, 67.4, 58.6, 55.9, 46.8, 28.0; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C23H23BrNO2, 424.0912, found, 424.0924.
Pictet−Spengler Reactions of p-Bromobenzaldehyde with
2-Nitrophenylsulfenyl Substituted Phenylethylamine 3: Opti-
mization Studies. The reactions were performed with amine 3 (0.02
mmol) and p-bromobenzaldehyde (0.03 mmol) in 0.2 mL of toluene.
The conversion of the bright yellow Nps-derivatives was conveniently
followed using TLC [silica gel, ethyl acetate/petroleum ether (v/v =
20/80−50/50) or dichloromethane/petroleum ether/ethyl acetate (v/
v/v = 50/50/2−50/50/4) as eluent]. HPLC samples for ee-
determination were prepared by scratching the yellow product spot
(8d) from the TLC-plate, followed by extraction of the silica gel with a
mixture of n-heptane/i-propanol (v/v = 85/15, ca. 0.1 mL), filtration
and direct analysis.
(S)-9c (3-Cl): yellow glass, 75% yield, 47% ee; tR (major) = 26.4
20
min, tR (minor) = 42.5 min; [α]D = +42.5 (c = 1.0, CHCl3); IR
(film) ν 3526, 2929, 1508 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.26
(d, J = 8.4 Hz, 1 H), 7.92 (d, J = 8.2 Hz, 1 H), 7.56 (t, J = 7.7 Hz, 1
H), 7.27−7.06 (m, 5 H), 6.79 (s, 1 H), 6.27 (s, 1 H), 5.61 (broad s, 1
H, OH), 5.18 (s, 1 H), 3.72 (s, 3 H), 2.8−3.7 (broad, 4 H); 13C NMR
(101 MHz, CDCl3) δ 145.2, 144.7, 142.0, 134.0, 133.7, 129.3, 129.2,
127.7, 127.5, 125.8, 124.9, 124.6, 114.3, 110.2, 55.9, 49.1; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C22H20ClN2O4S, 443.0832, found,
443.0832.
(S)-9d (4-Cl): yellow glass, 83% yield, 71% ee; after removal of the
crystalline racemate 57% yield, > 99% ee; tR (major) = 15.7 min, tR
20
(minor) = 20.9 min; [α]D = +104 (c = 1.0, CHCl3); IR (film) ν
3525, 1505, 728 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.3
Hz, 1 H), 7.94 (d, J = 8.2 Hz, 1 H), 7.56 (t, J = 7.7 Hz, 1 H), 7.23
(broad, 3 H), 7.15 (broad, 2 H), 6.79 (s, 1 H), 6.27 (s, 1 H), 5.66
(broad s, 1 H, OH), 5.19 (s, 1 H), 3.71 (s, 3 H), 3.44 (broad, 1 H),
3.29−3.04 (broad, 2 H), 2.99−2.83 (broad, 1 H); 13C NMR (101
MHz, CDCl3) δ 145.2, 144.7, 142.0, 133.8, 133.4, 130.6, 128.2, 127.2,
125.8, 124.8, 124.6, 114.2, 110.2, 55.9, 49.1; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C22H20ClN2O4S, 443.0832, found, 443.0821.
(S)-9e (4-OMe): yellow glass, 62% yield, 0% ee; tR = 19.2 min, tR =
General Procedure for the Pictet−Spengler Reaction of
Aromatic Aldehydes with N-2-Nitrophenylsulfenyl Substituted
Phenylethylamine 3. In a dry argon flushed flask Nps-protected
amine 3 (64.1 mg, 0.2 mmol), (R)-TRIP (15.0 mg, 10 mol %) and
(S)-BINOL (11.4 mg, 20 mol %) were dissolved in toluene (5 mL)
and stirred for 10 min under argon. The mixture was heated to 90 °C,
and the (substituted) benzaldehyde (0.30 mmol) added. The mixture
was stirred overnight at 90 °C while the azeotropic toluene/water
mixture was removed by a slow argon flow. The remaining solvent was
removed by rotary evaporation, and the crude mixture was purified by
flash chromatography [silica gel, dichloromethane/petroleum ether/
ethyl acetate (v/v/v = 50/50/2−50/50/4) as eluent]. Removal of the
solvent and coevaporation with dichloromethane (2−3 times to
remove residual ethyl acetate) leads to the pure products. If required,
recrystallization of the product to high enantiopurity was performed by
precipitation of the racemate from concentrated dichloromethane
solutions with petroleum ether. All Nps-protected tetrahydroisoquino-
1
26.2 min; IR (film) ν 3507, 2920, 1507 cm−1; H NMR (400 MHz,
CDCl3) δ 8.25 (d, J = 8.3 Hz, 1 H), 8.00 (d, J = 8.3 Hz, 1 H), 7.55 (t, J
= 7.6 Hz, 1 H), 7.21 (t, J = 7.7 Hz, 1 H), 7.12 (broad d, 2 H), 6.80
(broad d, 2 H), 6.78 (s, 1 H), 6.31 (s, 1 H), 5.17 (s, 1 H), 3.78 (s, 3
H), 3.70 (s, 3 H), 3.50 (broad, 1 H), 3.13 (m, 2 H), 2.87 (m, 1 H);
13C NMR (101 MHz, CDCl3) δ 159.0, 145.2, 144.6, 142.1, 133.7,
130.7, 130.5, 127.2, 125.7, 125.1, 124.4, 114.1, 113.9, 113.5, 113.4,
110.4, 55.9, 55.2, 48.7; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C23H23N2O5S, 439.1328, found, 439.1336.
1
lines were bright yellow, stable and readily purified. The H and 13C
(S)-9f (4-CF3): yellow glass, 79% yield, 86% ee; tR (major) = 14.5
min, tR (minor) = 21.2 min; [α]D20 = +70 (c = 0.87, CHCl3); IR (film)
NMR spectra, however, showed extreme line broadening for atoms in
the vicinity of the nitrogen−sulfur bond. The (S)-configuration was
assigned to the aryl-substituted tetrahydroisoquinolines in analogy
with 9d3b and is based on the (+) rotation and on the elution order in
chiral HPLC. Chiral HPLC: Chiralcel OD-H, n-heptane/i-propanol
(v/v = 70/30) as eluent, flow 0.5 mL/min, 254 nm. (S)-8d (4-Br):
yellow glass, 79% yield, 72% ee; after removal of the crystalline
racemate: 52% yield, >99% ee; tR (major) = 16.5 min, tR (minor) =
1
ν 3530, 2928, 1508 cm−1; H NMR (400 MHz, CDCl3) δ 8.26 (m, 1
H), 7.92 (d, J = 8.2 Hz, 1 H), 7.56 (m, 3 H), 7.20−7.40 (m, 3 H), 6.83
(s, 1 H), 6.28 (broad, 1 H), 5.64 (broad, 1 H), 5.31 (m, 1 H), 3.73 (s,
3 H), 3.46 (broad, 1 H), 3.10−3.30 (m, 2 H), 2.95−3.05 (m, 1 H);
13C NMR (101 MHz, CDCl3) δ 145.3, 144.9, 142.1, 133.8, 127.3,
127.0, 125.9, 125.15, 125.1, 125.0, 124.7, 124.1 (q, J = 273 Hz, CF3),
114.3, 110.1, 55.9, 49.1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C23H20F3N2O4S, 477.1096, found, 477.1097.
20
22.2 min. Data: [α]D = +107 (c = 1.04, CHCl3); IR (film) ν 3526,
2929, 1510, cm−1; 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.3 Hz,
1 H), 7.92 (d, J = 8.3 Hz, 1 H), 7.55 (ddd, J = 8.3, 7.0, 1.4 Hz, 1 H),
7.39 (broad d, J = 7.9 Hz, 2 H), 7.23 (ddd, J = 8.3, 7.2, 1.4 Hz, 1 H),
7.08 (broad d, J = 8.0 Hz, 2H), 6.79 (s, 1 H), 6.25 (s, 1 H), 5.59 (s, 1
H), 5.16 (broad s, 1 H), 3.71 (s, 3 H), 3.53−3.34 (m, 1 H), 3.21−3.05
(m, 2 H), 2.95−2.85 (m, 1 H); 13C NMR (101 MHz, CDCl3) δ 145.5,
145.0, 133.9, 131.4, 131.1, 127.5, 126.1, 125.0, 124.8, 121.8, 114.4,
110.4, 56.1, 49.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C22H20BrN2O4S, 487.0327, found, 487.0327.
(S)-9g (3-NO2): yellow glass, 85% yield, 28% ee; tR (major) = 28.4
min, tR (minor) = 51.1 min; [α]D20 = +33 (c = 1.0, CHCl3); IR (film)
1
ν 3530, 2928, 1508 cm−1; H NMR (400 MHz, CDCl3) δ 8.31 (m, 1
H) 8.2 (m, 2 H), 8.0 (m, 1 H), 7.64 (m, 2 H), 7.5−7.2 (m, 2 H), 6.87
(s, 1 H), 6.30 (s, 1 H), 5.7, (broad, 1 H, OH), 5.38 (s, 1 H), 3.75 (s, 3
H), 3.6−3.05 (m, 4 H); 13C NMR (101 MHz, CDCl3) δ 152.7, 148.0,
145.4, 144.9, 135.3, 133.9, 133.4, 131.2, 129.3, 129.0, 128.3, 127.3,
127.2, 125.7, 124.8, 124.6, 124.4, 122.6, 117.7, 114.5, 111.0, 110.7,
55.9, 52.5, 49.9, 36.1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C22H20N3O6S, 454.1073, found, 454.10669.
(S)-9a (Ph): yellow glass, 75% yield, 26% ee; tR (major) = 15.1 min,
20
tR (minor) = 19.8 min; [α]D = +18 (c = 0.5, CHCl3); IR (film) ν
(S)-9h (4- NO2): yellow glass, 51% yield, 68% ee; tR (major) = 32.7
min, tR (minor) = 50.2 min; [α]D20 = +74 (c = 0.98, CHCl3); IR (film)
1
3519, 2931, 1504, cm−1; H NMR (400 MHz, CDCl3) δ 8.28 (d, J =
1
ν 3503, 2933, 1510 cm−1; H NMR (400 MHz, CDCl3) δ 8.25 (m, 1
8.1 Hz, 1 H), 8.01 (d, J = 8.1 Hz, 1 H), 7.57 (m, 1 H), 7.18−7.36 (m,
6 H), 6.82 (s, 1 H), 6.34 (s, 1 H), 5.63 (broad s, 1 H, OH), 5.25
(broad, 1 H), 3.73 (s, 3 H), 2.8−3.7 (broad, 4 H); 13C NMR (101
MHz, CDCl3) δ 145.2, 144.7, 142.1, 133.7, 129.3, 128.1, 127.5, 127.3,
125.8, 125.1, 124.5, 114.2, 110.4, 55.9, 48.9; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C22H21N2O4S, 409.1222, found, 409.1218.
(S)-9b (2-Cl): yellow glass, 83% yield, 0% ee; tR = 14.3 min, tR =
H), 8.17−8.05 (m, 2 H), 7.88 (d, J = 8.2 Hz, 1 H), 7.56 (m, 1 H), 7.40
(d, J = 8.7 Hz, 2 H), 7.25 (m, 1 H), 6.81 (s, 1 H), 6.21 (broad, 1 H),
5.64 (broad, 1 H), 5.31 (broad, 1 H), 3.70 (s, 3 H), 2.9−3.5 (m, 4 H);
13C NMR (101 MHz, CDCl3) δ 147.2, 145.4, 145.0, 133.9, 130.0,
127.1, 126.0, 124.9, 124.5, 123.5, 114.4, 110.0, 55.9, 49.8; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C22H20N3O6S, 454.1073, found,
454.1071.
1
16.8 min; IR (film) ν 3521, 2930, 1507 cm−1; H NMR (400 MHz,
7386
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(S)-9i [3,4-(MeO)2]: yellow glass, 79% yield, 24% ee; tR (major) =
24.0 min, tR (minor) = 34.2 min; [α]D = +5 (c = 0.52, CHCl3); IR
by flash chromatography [silica gel, dichloromethane/petroleum
ether/ethyl acetate (v/v/v = 50/50/0.5−50/50/4) as eluent].
Removal of the solvent and coevaporation with dichloromethane
(2−3 times to remove residual ethyl acetate) led to the pure products.
Crystallization to high enantiopurity was performed by precipitation of
the major enantiomer (14) or the racemate (13 and 15) from
concentrated dichloromethane solutions with petroleum ether.
Compound 16 was crystallized to high enantiopurity after conversion
to 20. All Nps-protected tetrahydroisoquinolines were bright yellow,
stable compounds and readily purified. The 1H and 13C NMR spectra,
however, showed extreme line broadening for atoms in the vicinity of
the nitrogen−sulfur bond. Chiral HPLC: Chiralcel OD-H, n-heptane/
isopropanol (v/v = 70/30) as eluent, flow 0.5 mL/min, 254 nm. The
(R)-configuration of the alkyl-substituted tetrahydroisoquinolines was
determined as described in Schemes 3−6 and is further supported by
the negative rotation and the elution order in chiral HPLC.
20
(film) ν 3476, 2919, 1509 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.26
(d, J = 8.1 Hz, 1 H), 8.02 (broad d, J = 7.3 Hz, 1 H), 7.54 (m, 1 H),
7.22 (m, 1 H), 6.60−6.80 (m, 3 H), 6.32 (s, 1 H), 5.58 (broad, 1 H,
OH), 5.16 (broad, 1 H), 3.85 (s, 3 H), 3.74 (broad, 3 H), 3.71 (s, 3
H), 3.51 (broad, 1 H), 3.06−3.21 (m, 2 H), 2.83−2.95 (m, 1 H); 13C
NMR (101 MHz, CDCl3) δ 148.6, 148.4, 145.1, 144.6, 133.6, 127.2,
125.9, 125.1, 124.1, 121.8, 114.1, 112.4, 110.6, 110.4, 56.2, 55.9, 55.8,
48.9; HRMS (ESI-TOF) m/z [M + H]+ calcd for C24H25N2O6S,
469.1433, found, 469.1436.
(S)-9j (2-naphthyl): yellow glass, 80% yield, 64% ee; tR (major) =
20
18.7 min, tR (minor) = 22.8 min; [α]D = +75 (c = 1.0, CHCl3); IR
(film) ν 3526, 2915, 1564 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.26
(m, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 7.76−7.82 (m, 3 H), 7.78 (d, J =
8.2 Hz, 2 H), 7.57−7.54 (m, 2 H), 7.53−7.45 (m, 2 H), 7.44−7.7 (m,
8 H), 7.22 (m, 1 H), 6.86 (s, 1 H), 6.37 (s, 1 H), 5.64 (broad, 1 H),
5.41 (s, 1 H), 3.69 (s, 3 H), 3.40−3.60 (m, 1 H), 3.20 (m, 2 H), 2.92−
3.04 (m, 1 H); 13C NMR (101 MHz, CDCl3) δ 145.2, 144.6, 142.1,
133.7, 132.9, 132.8, 128.3, 128.1, 127.9, 127.5, 127.3, 126.1, 126.0,
124.5, 114.2, 110.5, 55.9, 48.8, 29.7, 27.1; HRMS (ESI-TOF) m/z [M
+ H]+ calcd for C26H23N2O4S, 459.1379, found, 459.1382.
(R)-12: yellow glass, 88% yield, 64% ee; tR (minor) = 11.7 min, tR
(major) = 13.3 min; [α]D20 = −7 (c = 1.3, CHCl3); IR (film) ν 3508,
2929, 1507 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.2 Hz,
1 H), 7.24−8.24 (m, 3 H), 6.72 (s, 1 H), 6.52 (s, 1 H), 5.32 (broad,
OH), 4.07 (m, 1 H), 3.89 (s, 3 H), 2.6−3.75 (m, 4 H), 1.75−1.87 (m,
2 H), 1.30 (m, 4 H), 0.88 (m, 3 H); 13C NMR (101 MHz, CDCl3) δ
144.2, 133.7, 125.8, 124.8, 124.4, 114.5, 109.2, 66.6, 56.0, 31.5, 22.6,
14.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H27N2O4S,
403.1692, found, 403.1697.
(S)-1-(4-Chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline (10). A mixture of 9d (39.6 mg, 0.11 mmol, >99% ee),
iodomethane (20 μL, 0.32 mmol) and K2CO3 (60 mg, 0.43 mmol) in
acetonitrile (1.5 mL) was stirred overnight in a stoppered flask at 80
°C. The product obtained after extractive workup (water/CH2Cl2) was
dissolved in a mixture of CH2Cl2 (1 mL) and EtOH (1 mL) at 0 °C,
and concentrated HCl (100 μL) was added. The reaction was stirred
at this temperature for 3 h and quenched by addition of a
semisaturated Na2CO3 solution (20 mL). Extraction with ethyl acetate
and purification by flash chromatography [silica gel, petroleum ether/
ethyl acetate (v/v = 50/50−0/100) and ethyl acetate/methanol (v/v =
90/10) as eluent] gave tetrahydroisoquinoline 10 (23.6 mg, 0.080
mmol, 88%) as a white solid: mp 112−115 °C; [α]D20 = −31 (c = 0.61,
CHCl3); IR (film) ν 2925, 1513 cm−1; 1H NMR (400 MHz, CDCl3) δ
7.28 (d, J = 8.2 Hz, 2 H), 7.19 (d, J = 8.2 Hz, 2 H), 6.62 (s, 1 H), 6.19
(s, 1 H), 5.02 (s, 1 H), 3.87 (s, 3 H), 3.64 (s, 3 H), 3.23−3.14 (m, 1
H), 3.08−2.99 (m, 1 H), 2.96−2.87 (m, 1 H), 2.79−2.69 (m, 1 H);
13C NMR (101 MHz, CDCl3) δ 147.6, 147.0, 143.3, 133.0, 130.1,
(R)-13: Prepared from tert-butyl 4-oxobutanoate,22 yellow glass,
88% yield, 67% ee; after removal of the crystalline racemate 57% yield,
99% ee; chiral HPLC Chiralpak AD, n-heptane/isopropanol (v/v =
70/30) as eluent, flow 1.0 mL/min, 254 nm; tR (minor) = 10.8 min, tR
20
(major) = 12.8 min; [α]D = −13 (c = 0.76, CHCl3); IR (film) ν
3495, 2930, 1722, 1510 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.32 (d,
J = 8.2 Hz, 1 H), 7.2−8.2 (broad, 3 H), 6.73 (s, 1 H), 6.59 (s, 1 H),
5.58 (s, 1 H), 4.14 (broad, 1 H), 3.89 (s, 3 H), 2.5−3.7 (broad, 4 H),
2.25−2.50 (broad, 2 H), 2.0−2.3 (broad, 2 H), 1.39 (s, 9 H); 13C
NMR (101 MHz, CDCl3) δ 172.7, 145.1, 144.4, 133.8, 125.9, 124.5,
114.9, 109.2, 80.3, 56.0, 32.6, 27.9; HRMS (ESI-TOF) m/z [M + H]+
calcd for C23H29N2O6S, 461.1746, found, 461.1747.
(R)-14: yellow glass, 84% yield, 72% ee; after crystallization of the
major enantiomer 59% yield, >99% ee; tR (minor) = 24.1 min, tR
20
(major) = 30.8 min; mp 143.5−145.5 °C; [α]D = −42 (c = 1.0,
1
CHCl3); IR (film) ν 3514, 2932, 1510 cm−1; H NMR (400 MHz,
129.2, 128.4, 127.6, 111.4, 110.6, 60.7, 55.8, 55.7, 41.7, 29.1; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C17H19ClNO2, 304.1104, found,
304.1117.
CDCl3) δ 8.33 (d, J = 8.0 Hz, 1 H), 6.7−8.3 (broad, 8 H), 6.75 (s, 1
H), 6.50 (s, 1 H), 5.67 (bs, OH), 4.17 (broad, 1 H), 3.87 (s, 3 H), 3.79
(s, 3 H), 2.6−3.7 (broad, 6 H), 2,2 (broad, 2 H); 13C NMR (101
MHz, CDCl3) δ 157.7, 145.0, 144.3, 133.9, 133.8, 129.1, 126.0, 124.7,
124.5, 114.5, 113.8, 109.1, 56.0, 55.2; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C25H27N2O5S, 467.1641, found, 467.1657. Anal. Calcd
for C25H26N2O5S: C, 64.36; H, 5.62; N, 6.00. Found: C, 64.04; H,
5.76; N, 6.14.
N-Acetyl-1-(4-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahy-
droisoquinoline (11). A solution of 10 (46.1 mg, 0.15 mmol) and
acetic anhydride (18 μL) was stirred in CHCl3 (4 mL) at room
temperature for 2 h. Extractive workup (aqueous Na2CO3/ethyl
acetate) and chromatography (silica gel, petroleum ether/ethyl acetate
(v/v = 50/50−0/100 as eluent) gave 6 (32.2 mg, 0.090 mmol, 61%) as
a glass: [α]D20 = +224 (c = 1.1, CHCl3), [literature value for the (R)-
(R)-15: yellow glass, 75% yield, 33% ee; after removal of the
crystalline racemate 26% yield, 95% ee; chiral HPLC Chiralcel OD-H,
n-heptane/isopropanol (v/v = 70/30) as eluent, flow 0.6 mL/min tR
3c
20
1
enantiomer [α]D = −206 (c = 1.02, CHCl3), 98% ee] ; H NMR
(400 MHz, CDCl3, 5/1 mixture of rotamers, the major rotamer is
shown) δ 7.24 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 6.87 (s,
1H), 6.70 (s, 1H), 6.52 (s, 1H), 3.92 (s, 3H), 3.79 (s, 3H), 3.73−3.80
(m, 1H), 3.38 (ddd, J = 16.0, 11.8, 3.3 Hz, 1H), 2.98 (ddd, J = 16.4,
11.8, 5.8, 1H), 2.72−2.83 (m, 1H), 2.20 (s, 3H); 13C NMR (101 MHz,
CDCl3, mixture of rotamers, the major rotamer is shown, 2 aromatic
carbon signals not observed, δ 168.9, 148.6, 148.2, 133.4, 130.1, 128.4,
126.8, 126.3, 111.7, 56.1, 56.05, 54.0, 40.3, 28.6, 21.5. HRMS (ESI-
TOF) m/z [M + H]+ calcd for C19H21ClNO3, 346.1210, found,
346.1208.
20
(minor) = 14.5 min, tR (major) = 17.4 min; [α]D = −38 (c = 0.9,
1
CHCl3); IR (film) ν 3510, 2929, 1510 cm−1; H NMR (400 MHz,
CDCl3) δ 8.34 (d, J = 7.8 Hz, 1 H), 7.2−8.3 (broad, 8 H), 6.76 (s, 1
H), 6.50 (s, 1 H), 5.60 (s, 1 H, OH), 4.20 (broad, 1 H), 3.87 (s, 3 H),
2.2−3.75 (broad, 6 H), 2.19 (broad, 2 H); 13C NMR (101 MHz,
CDCl3) δ 146.1, 144.4, 133.9, 128.6, 126.2, 125.3, 125.2, 124.6,
124.55, 114.5, 108.9, 56.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C25H24F3N2O4S, 505.1409, found, 505.1413.
(R)-16: yellow glass; reaction conditions, rt, addition of the
aldehyde over 6 h, 92% yield, 58% ee; removal of the crystalline
racemate was performed with 20, see below; chiral HPLC Chiralpak
AD, n-heptane/isopropanol (v/v = 70/30) as eluent, flow 1.0 mL/min,
254 nm; tR (minor) = 17.8 min, tR (major) = 22.1 min; [α]D20 = −14
(c = 0.71, CHCl3); IR (film) ν 3460, 2925, 1737, 1509 cm−1; 1H NMR
(400 MHz, CDCl3) δ 8.31 (d, J = 8.1 Hz, 1 H), 7.2−8.3 (broad, 3 H),
6.74 (s, 1 H), 6.62 (s, 1 H), 5.71 (broad, OH), 4.25−4.5 (broad, 3 H),
3.87 (s, 3 H), 2.5−3.7 (broad, 4 H), 2.02 (s, 3 H); 13C NMR (101
MHz, CDCl3) δ 144.9, 133.6, 127.6, 125.7, 124.6, 124.2, 114.7, 111.9,
General Procedure for the Pictet−Spengler Reaction of
Aliphatic Aldehydes with N-2-Nitrophenylsulfenyl Substituted
Phenylethylamine 3. In a dry argon flushed flask Nps-protected
amine 3 (64.1 mg, 0.2 mmol), (R)-TRIP (7.6 mg, 5 mol %) (S)-
BINOL (11.4 mg, 20 mol %) and acetic acid (5.7 μL, 50 mol %) were
dissolved in toluene (5 mL) and stirred for 10 min under argon before
the aldehyde (0.30 mmol) was added. The mixture was stirred during
the indicated time at 80 °C in a stoppered flask. The remaining solvent
was removed by rotary evaporation, and the crude mixture was purified
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109.3, 66.7, 65.8, 64.6, 55.9, 47.2, 25.7, 21.0; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C19H21N2O6S, 405.1120, found, 405.1126.
Pyrrolo-tetrahydroisoquinolidone 17. Acetyl chloride (71.4 μL,
1.0 mmol) was added to dry ethanol (1.5 mL) at 0 °C. After 15 min
this solution was added in one portion to a stirred solution of 13 (98%
ee, 43.0 mg, 0.093 mmol) in CH2Cl2 (1.5 mL) at 0 °C. The reaction
was stirred at this temperature for 1 h and quenched by addition of a
semisaturated Na2CO3 solution (20 mL). Extraction with ethyl acetate
and evaporation gave crude product, which was cyclized in xylene
(mixture of isomers, 5 mL) containing triethylamine (100 μL) for 16 h
at 130 °C under argon. (Removal of the side product Nps-OEt before
cyclization resulted in considerable tetrahydroquinoline oxidation!)
Purification by flash chromatography [silica gel, petroleum ether/ethyl
acetate (v/v = 50/50−0/100) and ethyl acetate/methanol (v/v = 90/
CDCl3) δ 148.2, 147.6, 134.1, 127.0, 126.1, 124.7, 111.6, 109.8, 56.0,
55.9.
(R)-(−)-Calycotomine (21). Acetyl chloride (71.4 μL, 1.0 mmol)
was added to dry ethanol (1.5 mL) at 0 °C. After 15 min this solution
was added in one portion to a stirred solution of 20 (97% ee, 18.0 mg,
0.048 mmol) and thiophenol23 (15 μL, 0.15 mmol) in CH2Cl2 (1.5
mL) at 0 °C. After stirring at this temperature for 20 min the reaction
was quenched by the addition of triethylamine (0.2 mL), and the
solvents were evaporated. Chromatography [silica gel, ethyl acetate−
ethyl acetate/methanol/conc. NH4OH (v/v/v = 90/7/3−82/14/4) as
eluent gave (R)-(−)-calycotomine 21 (10.0 mg, 0.045 mmol, 94%) as
a solid: mp 139−141 °C; [α]D20 = −33 (c = 0.83, water), lit14a [α]D
20
= −33.7 (c = 1.05, water) 96% ee; IR (film) ν 2600−3200 (broad),
1
1515 cm−1; H NMR (400 MHz, CDCl3) δ 6.60 (s, 1 H), 6.59 (s, 1
20
H), 5.5 (broad, OH), 3.99 (dd, J = 9.2, 4.2 Hz, 1 H), 3.86 (s, 3 H),
3.86 (s, 3 H), 3.78 (dd, J = 10.8, 4.3 Hz, 1 H), 3.64 (dd, J = 10.8, 9.3
Hz, 1 H), 3.0−3.15 (m, 1 H), 2.65−2.75 (m, 2 H); 13C NMR (101
MHz, CDCl3) δ 147.7, 147.4, 127.8, 127.5, 111.9, 109.1, 70.9, 64.0,
56.0, 55.8, 38.7, 37.2, 29.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C12H18NO3, 224.1287, found, 224.1295.
10) as eluent] gave 17 (16.5 mg, 0.071 mmol, 76%) as a glass: [α]D
= +254 (c = 0.83, CHCl3); IR (film) ν 3200 (broad), 2971, 1665
cm−1; 1H NMR (400 MHz, CDCl3) δ 6.71 (s, 1 H), 6.56 (s, 1 H), 5.88
(broad, OH), 4.73 (m, 1 H), 4.26 (ddd, J = 15.1, 6.0, 2.3 Hz, 1 H),
3.89 (s, 3 H), 3.02 (m, 1 H), 2.86 (m, 1 H), 2.4−2.7 (m, 4 H), 1.85
(m, 1 H); 13C NMR (101 MHz, CDCl3) δ 173.2, 145.8, 144.5, 128.7,
126.3, 114.7, 106.9, 56.6, 56.0, 37.1, 31.8, 27.9, 27.8; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C13H16NO3, 234.1130, found,
234.1138.
(R)-(+)-Colchietine (22). Conc. HCl (150 μL) was added to a
solution of (R)-14 (99% ee, 70.0 mg, 0.15 mmol) in a mixture of
CH2Cl2 (3 mL) and ethanol (3 mL) at 0 °C. The reaction was stirred
at this temperature for 75 min and quenched by addition of a
semisaturated Na2CO3 solution (20 mL). Extraction with ethyl acetate
and purification by flash chromatography [silica gel, ethyl acetate and
ethyl acetate/methanol/conc. NH4OH (v/v/v = 88/10/2) as eluent]
gave (R)-(+)-N-demethyl-colchietine (43.0 mg, 0.136 mmol, 91%) as
O-Methylation of 17 to 18. A mixture of 17 (15.0 mg, 0.064
mmol), iodomethane (20 μL, 0.32 mmol) and K2CO3 (60 mg, 0.43
mmol) in acetonitrile (1.5 mL) was stirred overnight in a stoppered
flask at 80 °C. Extractive workup (water/ethyl acetate) and
chromatography [silica gel, ethyl acetate and ethyl acetate/methanol
(v/v = 95/5) as eluent] gave 18 (14.1 mg, 0.057 mmol, 89%) as a
20
a solid: [α]D = +37.5 (c = 0.85, CHCl3), 1H NMR (400 MHz,
20
CDCl3) δ 7.16 (d, J = 8.6 Hz, 2 H), 6.86 (d, J = 8.7 Hz, 2 H), 6.62 (s,
1 H), 6.56 (s, 1 H), 4.0 (m, 1 H), 3.83 (s, 3 H), 3.81 (s, 3 H), 3.6−3.9
(broad, NH, OH); 3.25 (m, 1 H), 3.00 (m, 1 H), 2.6−2.85 (m, 4 H),
2.0−2.2 (m, 2 H); 13C NMR (101 MHz, CDCl3) δ 157.7, 145.2,
144.0, 134.2, 130.2, 129.2, 127.7, 114.9, 113.8, 108.5, 56.0, 55.2, 55.1,
40.8, 38.4, 31.4, 29.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C19H24NO3, 314.1756, found, 314.1771.
glass: [α]D = +216 (c = 0.6, CHCl3); IR (film) ν 2926, 1664 cm−1;
1H NMR (400 MHz, CDCl3) δ 6.63 (s, 1 H), 6.58 (s, 1 H), 4.74 (m,
1H), 4.31 (ddd, J = 14.8, 6.1, 2.2 Hz, 1 H), 3.88 (s, 3 H), 3.87 (s, 3 H),
3.02 (m, 1 H), 2.90 (m, 1 H), 2.4−2.7 (m, 4 H), 1.84 (m, 1 H); 13C
NMR (101 MHz, CDCl3) δ 173.1, 148.1, 147.9, 129.3, 125.5, 111.6,
107.6, 56.5, 56.0, 55.9, 37.0, 31.8, 28.1, 27.7.
(R)-(+)-Crispine A (19). Lactam 18 (16.0 mg, 0.065 mmol) was
Reductive methylation: (R)-(+)-N-demethyl-colchietine (41.7 mg,
0.133 mmol), paraformaldehyde (24.0 mg, 0.8 mmol), zinc chloride
(13 mg) and sodium cyanoborohydride (16.0 mg, 0.25 mmol) were
stirred in methanol (7 mL) overnight. Silica gel was added, the solvent
was removed and chromatography [silica gel, ethyl acetate and ethyl
acetate/methanol/conc. NH4OH (v/v/v = 92/6/2) as eluent] gave
(R)-(+)-colchietine 22 (40.1 mg, 0.123 mmol, 92%) as a syrup: ee
98%, Chiralcel OD-H, n-heptane/isopropanol (v/v = 70/30) as eluent,
flow 0.5 mL/min, 254 nm; tR (minor) = 10.9 min, tR (major) = 12.5
min; [α]D20 = +8 (c = 0.80, CHCl3), [α]D20 = 0 (c = 0.80, methanol),
lit15 [α]D20 = +8 (c = 1.0, methanol); IR (film) ν 2925, 1511 cm−1; 1H
NMR (400 MHz, CDCl3) δ 7.12 (d, J = 6.7 Hz, 2 H), 6.84 (d, J = 6.7
Hz, 2 H), 6.66 (s, 1 H), 6.52 (s, 1 H), 3.85 (s, 3 H), 3.80 (s, 3 H), 3.49
(m, 1 H), 3.21 (m, 1 H), 2.65−2.85 (m, 4 H), 2.55−2.65 (m, 1 H),
2.52 (s, 3 H), 1.95−2.2 (m, 2 H); 13C NMR (101 MHz, CDCl3) δ
157.6, 145.1, 144.0, 134.6, 129.3, 128.6, 126.8, 114.3, 113.7, 109.4,
62.7, 56.0, 55.2, 47.6, 42.3, 37.1, 30.8, 24.7; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C20H26NO3, 328.1913, found, 328.1927.
(R)-(+)-[1-(p-Methoxyphenyethyl)]-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (23). A mixture of 14 (68.0 mg, 0.146
mmol, >99% ee), iodomethane (40 μL, 0.64 mmol) and K2CO3 (120
mg, 0.86 mmol) in acetonitrile (3 mL) was stirred overnight in a
stoppered flask at 80 °C. The product obtained after extractive workup
(water/CH2Cl2) was dissolved in CH2Cl2 (2.5 mL) at 0 °C and an ice
cold solution of HCl in ethanol (prepared from acetyl chloride (0.107
mL) and dry ethanol (2.5 mL) was added. The reaction was stirred at
this temperature for 75 min and quenched by addition of a
semisaturated Na2CO3 solution (20 mL). Extraction with ethyl acetate
and purification by flash chromatography [silica gel, ethyl acetate and
ethyl acetate/methanol/conc. NH4OH (v/v/v = 90/8/2) as eluent]
gave tetrahydroisoquinoline 23 (39.2 mg, 0.12 mmol, 82%) as a glass:
[α]D20 = +14 (c = 0.5, CHCl3), lit17 [α]D20 = +20.5 (c = 1.0, CHCl3);
IR (film) ν 2932, 1511 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.17 (d,
J = 8.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 6.60 (s, 1 H), 6.59 (s, 1 H),
reduced with lithium aluminum hydride (1 M in THF, 0.15 mL) as
described in the literature13f to give (R)-(+)-crispine A (11.7 mg,
20
0.050 mmol, 77%) as a slowly solidifying oil: mp 53−57 °C; [α]D
=
20
+93 (c = 0.19, CHCl3), Lit. several values are reported between [α]D
13
20
1
+90 and [α]D +100 ; IR (film) ν 2925, 1512 cm−1; H NMR (400
MHz, CDCl3) δ 6.63 (s, 1 H), 6.58 (s, 1 H), 3.87 (s, 3 H), 3.86 (s, 3
H), 3.42 (m, 1 H), 3.20 (ddd, J = 14.0, 6.3, 2.8 Hz, 1 H), 3.0−3.25 (m,
2 H), 2.75 (bd, J = 17.4 Hz, 1 H), 2.65 (ddd, J = 11.0, 10.4, 4.8 Hz, 1
H), 2.56 (m, 1 H), 2.34 (m, 1 H), 1.8−2.0 (m, 2 H), 1.74 (m, 1 H);
13C NMR (101 MHz, CDCl3) δ 147.3, 147.25, 131.0, 126.2, 111.3,
108.8, 63.0, 56.0, 55.8, 53.1, 48.3, 30.4, 28.1, 22.2; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C14H20NO2, 234.1494, found, 234.1505.
1-Hydroxymethyl-N-Nps-6,7-dimethoxy-1,2,3,4-tetrahydroi-
soquinoline (20). Pictet−Spengler product 16 (from 0.10 mmol 3)
was without purification converted into 20 in two steps. First, product
16, iodomethane (20 μL, 0.32 mmol) and K2CO3 (60 mg, 0.43 mmol)
in acetonitrile (1.5 mL) were stirred overnight in a stoppered flask at
80 °C. The suspension was then cooled to rt, and additional K2CO3
(90 mg, 0.65 mmol) and methanol (3 mL) were added, and stirring
was continued for 3 h. Extractive workup (water/ethyl acetate) and
chromatography [silica gel, petroleum ether/ethyl acetate (v/v = 50/
50) as eluent] gave 20 (33.3 mg, 0.089 mmol, 89% over three steps) as
a glass. Crystallization to increase enantiopurity was achieved by
coevaporation with dichloromethane followed by precipitation of the
racemate from a concentrated dichloromethane solution by adding
petroleum ether. Concentration of the filtrate in vacuo gave 20 as a
yellow glass: 19.7 mg, 52% yield (over 3 steps), 97% ee; Chiralpak AD,
n-heptane/isopropanol (v/v = 70/30) as eluent, flow 1.0 mL/min, 254
nm; tR (minor) = 10.7 min, tR (major) = 13.5 min; [α]D20 = −14 (c =
1
0.71, CHCl3); IR (film) ν 3511, 2934, 1506 cm−1; H NMR (400
MHz, CDCl3) δ 8.31 (d, J = 8.2 Hz, 1 H), 7.3−7.7 (broad, 3 H), 6.69
(s, 1 H), 6.64 (s, 1 H), 42.4 (m, 1 H), 3.90 (s, 3 H), 3.87 (s, 3 H),
2.7−4.0 (broad, 6 H), 1.92 (broad, OH); 13C NMR (101 MHz,
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3.96 (m, 1 H), 3.87 (s, 3 H), 3.85 (s, 3 H), 3.80 (s, 3 H), 3.17 (m, 1
H), 3.01 (m, 1 H), 2.65−2.85 (m, 4 H), 1.95−2.15 (m, 2 H); 13C
NMR (101 MHz, CDCl3) δ 157.7, 147.2, 147.1, 134.3, 131.3, 129.2,
127.2, 113.8, 111.7, 109.1, 55.9, 55.7, 55.2, 55.0, 41.0, 38.4, 31.5, 29.4;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H26NO3, 328.1913,
found, 328.1929.
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(R)-(+)-Almorexant Precursor 24. A mixture of 15 (filtrate of the
crystallization, 95% ee, 68.0 mg, 0.146 mmol), iodomethane (30 μL,
0.48 mmol) and K2CO3 (100 mg, 0.72 mmol) in acetonitrile (2 mL)
was stirred overnight in a stoppered flask at 80 °C. The product
obtained after extractive workup (water/CH2Cl2) was dissolved in
CH2Cl2 (1.5 mL) at 0 °C, and an ice cold solution of HCl in ethanol
(prepared from 71.4 μL acetyl chloride and 1.5 mL dry ethanol) was
added. The reaction was stirred at this temperature for 75 min and
quenched by addition of a semisaturated Na2CO3 solution (20 mL).
Extraction with ethyl acetate and purification by flash chromatography
[silica gel, ethyl acetate and ethyl acetate/methanol/conc. NH4OH (v/
v/v = 93/5/2) as eluent] gave tetrahydroisoquinoline 2420 (39.2 mg,
0.12 mmol, 82%) as a glass: [α]D20 = +8 (c = 1.0, CHCl3); IR (film) ν
2932, 1511 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.0 Hz,
2 H), 7.56 (d, J = 8.0 Hz, 2 H), 6.60 (s, 1 H), 6.58 (s, 1 H), 3.99 (m, 1
H), 3.87 (s, 3 H), 3.85 (s, 3 H), 3.25 (m, 1 H), 3.03 (m, 1 H), 2.70−
2.95 (m, 4 H), 1.95−2.05 (m, 2 H); 13C NMR (101 MHz, CDCl3),
CF3 not observed, δ 147.4, 147.2, 146.6, 130.8, 128.7, 127.3, 125.3,
111.8, 109.0, 56.0, 55.8, 54.9, 40.9, 37.9, 32.2, 29.4; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C20H23F3NO2, 366.1681, found, 366.1699.
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Org. Chem. 2011, 76, 534. (k) Amat, M.; Elias, V.; Llor, N.; Subrizi, F.;
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ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra and HPLC analyses for ee
determination. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: h.hiemstra@uva.nl.
Notes
The authors declare no competing financial interest.
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dx.doi.org/10.1021/jo501099h | J. Org. Chem. 2014, 79, 7380−7390

The Journal of Organic Chemistry
Article
(23) Thiophenol was added as Nps-scavenger to prevent intra-
molecular N- to O-sulfenyl transfer.
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dx.doi.org/10.1021/jo501099h | J. Org. Chem. 2014, 79, 7380−7390