Synthesis of Tetrahydroisoquinoline Alkaloids and Related Compounds through the Alkylation of Anodically Prepared α-Amino Nitriles

Article abstract of DOI:10.1021/acs.joc.6b01419

α-Amino nitrile 2a was conveniently prepared in two individual steps from chiral hexafluorophosphate salt isoquinolinium (-)-8b including anodic cyanation as an efficient means to activate the sp³ C1-H bond of the THIQ nucleus. The lithiation o

Full text of DOI:10.1021/acs.joc.6b01419

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Article
Synthesis of Tetrahydroisoquinoline Alkaloids and Related Compounds
Through the Alkylation of Anodically Prepared alpha-Amino nitriles.
Lotfi Benmekhbi, Fadila Louafi, Thierry Roisnel, and Jean-Pierre Hurvois
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01419 • Publication Date (Web): 13 Jul 2016
Downloaded from http://pubs.acs.org on July 13, 2016
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Synthesis of Tetrahydroisoquinoline Alkaloids and Related
Compounds Through the Alkylation of Anodically
Prepared α-Amino nitriles.
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§
†
‡
‡
Lotfi Benmekhbi, Fadila Louafi, Thierry Roisnel, JeanꢀPierre Hurvois. *
§
Laboratoire de Chimie des Matériaux, Faculté des Sciences Exactes, Université de
Constantine1, route de Ain El Bey, 25000 Constantine, Algérie
†
Unité de Recherche CHEMS, Faculté des Sciences Exactes, Université de Constantine1,
route de Ain El Bey, 25000 Constantine, Algérie
‡
Sciences Chimiques de Rennes, UMR 6226, CNRS–Université de Rennes 1, 2 Avenue
Léon Bernard, 35043, Rennes Cedex, France.
PF6
2
steps
4 steps
N
Ph
Me
N
Ph
N
Boc
CN Me
R1
(
–)-8b
2a, 65%, 60:40 dr
(+)ꢀ10a–g, up to 99:1 er
MeO
MeO
MeO
MeO
MeO
4
steps
4 steps
(–)ꢀ2b
N
Ph
CN Me
(+)ꢀ2b, 99:1 dr, Xꢀray
N
N
MeO
Me
Me
(
+)ꢀcarnegine,
OMe
99:1 er
OMe
(
–)ꢀxylopinine, 99:1 er, Xꢀray
αꢀAmino nitrile 2a was conveniently prepared in two individual steps from chiral
hexafluorophosphate salt isoquinolinium (–)ꢀ8b including anodic cyanation as an
3
efficient mean to activate the sp C1–H bond of the THIQ nucleus. The lithiation of 2a
was carried out in THF at –80 °C in the presence of LDA to produce a stable αꢀamino
carbanion which was condensed on a large variety of alkyl halides. The resulting
quaternary αꢀamino nitriles were subjected to a stereoselective reductive
decyanation in ethanol in the presence of NaBH
4
as the hydride donor to yield NꢀBocꢀ
1
ꢀalkylꢀTHIQs (+)ꢀ10a–g in up to 97:3 er’s after removal of the chiral auxiliary group.
Examination of the ORTEP view of THIQ (+)ꢀ1f revealed that the newly created
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stereogenic center had an absolute S configuration. Likewise, (–)ꢀxylopinine was
synthesized in four workꢀup steps in an overall 63% yield from αꢀamino nitrile (+)ꢀ2b.
In this process, crystallization of an enantioenriched mixture (90:10) of (–)ꢀ
norlaudanosine with 1 equiv of (–)ꢀNꢀacetylꢀLꢀleucine afforded the leucinate salt (+)ꢀ
13 (99:1 dr). Similarly, (+)ꢀsalsolidine was displaced from its (–)ꢀDBTA salt (–)ꢀ12 in
0
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99:1 er, which was determined by proton and carbon NMR spectroscopy in the
presence of thiophosphinic acid (+)ꢀ14 as the chiral solvating agent.
INTRODUCTION
Isoquinolines form a large group of compounds which are found in nature and in
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pharmaceuticals. 1ꢀAlkylꢀtetrahydroisoquinolines (1ꢀalkylꢀTHIQs, 1) are a subclass
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of isoquinolines occurring in at least 20 families of the plant kingdom. Apart from
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their significance in biosynthesis, these compounds also display a broad range of
interesting biological activities. For example, numerous 1ꢀbenzylꢀTHIQs were shown
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to act as ligands of calcium activated potassium channels. They also shown to
selectively inhibit the Orexin system which is involved in feeding behavior and
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insomnia. Many derivatives showed potentiation of NMDA glutamate receptors
which play a prominent role in brain processes such as neuronal plasticity and
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synaptic communication. So, approaches allowing the stereoselective syntheses of
1ꢀalkylꢀTHIQs are of great value and rely on one of three strategies that are drawn on
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scheme 1.
The first approach (Eq.1, i) is based on diastereoselective hydride reduction of
the C1–N2 double bond of 1ꢀalkylꢀ3,4ꢀdihydroisoquinolinium salts which are readily
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prepared by a Bischler–Napieralski cyclization. Similarly, asymmetric transfer
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hydrogenation with chiral Ru, Rh, or Ir complexes has become a wellꢀestablished
method that allowed an efficient control of the absolute configuration of the C1
carbon. Asymmetric Pictet–Spengler cyclization (Eq.2, ii) between a βꢀarylethylamine
and an aldehyde, in which the control of the absolute configuration of the C1 carbon
atom is performed during the cyclization process, has also been successfully
employed for the synthesis of THIQ alkaloids; it is worthy of note that
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enantioselective approaches have been recently reported.
However, both
approaches are not completely satisfactory since they required the presence of
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1 2
electronꢀrich aryl groups (ie. R = R = OMe) in the molecule for the construction of
the future C8a–C1 bond.
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Scheme 1. General approaches for stereoselective syntheses of 1ꢀalkylꢀTHIQs.
This problem can be avoided by using the bond disconnection between the THIQ
ring and the C1 substituent. This soꢀcalled C1–Cα connectivity approach (Eq.3) can
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be achieved through the diastereoꢀ or enantioselective additions of carbon
nucleophiles on the azomethine bond of the isoquinoline ring (Eq.3, iii) or through the
alkylation of dipoleꢀstabilized anions obtained from the deprotonation of THIQs (Eq.3,
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iv) in which the chiral auxiliary is appended by the N2 or C3 atoms. However, the
condensation of such αꢀaminoꢀorganolithium species with alkyl halides has proven to
be somewhat problematic due to the presence of an unwanted single electron or
elimination processes which limit this approach to a restricted number of
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electrophiles. To overcome this drawback, the use of lithiated 1ꢀcyanoꢀstabilized
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THIQs seemed a promising possibility which has been little studied to date. This is
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surprising since in the last decade, several catalytic, visibleꢀlight photoredox
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approaches, and stoichiometric oxidants such as DDQ, PhI(OAc)2, 1ꢀcyanoꢀ
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3(1H)ꢀ1,2ꢀbenziodoxols,
tetrahydroisoquinolineꢀ1ꢀcarbonitriles. However, the aboveꢀmentioned methods have
a limited substrate scope due to the fact that cleavage of the Nꢀaryl bond (R = Ph) in
the late stage of the syntheses could only be achieved under Birch type conditions.
have been utilized for the synthesis of 2ꢀarylꢀ
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On the other hand, examples of oxidation of tertiary aliphatic amines are scarce.
As far as the αꢀcyanation of natural products is concerned, Sundberg reported the
synthesis of 3ꢀcyanocatharantine in the presence of DDQ and 3 equiv of TMSCN,
and a photoredox catalytic version of this study has been recently reported by
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Stephenson. 12ꢀCyanogalanthamine was obtained by Hametner by the successive
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treatment of galanthamine with Nꢀbromosuccinimide and KCN.
In this area of research, we reported the synthesis of the pyrroloisoquinoline
alkaloid (+)ꢀcrispine A from a stable THIQ αꢀamino nitrile, prepared by
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electrochemical means. Yet, anodic cyanation and alkylation of metallated αꢀamino
nitriles seemed to be a quite general approach for the formation of new carbon to
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carbon bonds in the C1 position of the THIQ nucleus. In addition, the presence of
an αꢀphenylethylamine group (αꢀPEA) linked to the nitrogen atom allowed an efficient
1ꢀ3ꢀstereoinduction during the reductive decyanation process. The objectives of the
present study were twoꢀfold. Firstly, we wish to widen the scope of our
electrochemical approach for the synthesis of natural optically active THIQs
derivatives such as (+)ꢀsalsolidine or (–)ꢀxylopinine (figure 1); secondly, to investigate
the chemistry of αꢀamino nitrile 2a which complements the existing methods reported
for the synthesis of pyrrolo[2,1ꢀa]ꢀisoquinoline (–)ꢀ3 and tetrahydroberberine (–)ꢀ4,
analogous to (–)ꢀcrispine and (–)ꢀxylopinine, respectively.
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Figure 1. Natural and synthetic THIQs.
RESULTS AND DISCUSSION
Synthesis of THIQs (+)-6a,b. We set the intermediary THIQs (+)ꢀ6a,b as
initial synthetic targets according to the two distinct protocols depicted in scheme 2.
The synthesis of THIQ (+)ꢀ6b was carried out according to the procedure which has
2
6a
been reported in a previous work from this laboratory.
Thus, treatment of βꢀ
phenylethylamine (–)ꢀ5 in the presence of a mixture of formic acid, and paraꢀ
formaldehyde proved to be the most straightforward access to synthesize the
expected THIQ (+)ꢀ6b which was obtained in an overall 75% yield. In lieu of an
impracticable PictetꢀSpengler cyclization necessitating alkoxy or hydroxyl
substituents on the aromatic ring, we decided to utilize chiral isoquinolinium salt 8a
which was formerly employed by Marazano in a stereoselective access to 1ꢀalkylꢀ
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THIQs. Thus, the treatment of Zincke salt 7 with (S)ꢀ(–)ꢀαꢀPEA in dichloromethane
in the presence of 1.2 equiv of diethylamine for 48 h, provided the intermediary
pyridinium chloride salt 8a. For subsequent chemical manipulations, the chloride salt
8a was displaced from its chloride counterpart upon the addition of a concentrated
solution of HPF onto an aqueous solution of 8a to yield the hexafluorophosphate (–)ꢀ
6
8b which was recovered in an overall 70% yield from 7. The borohydride reduction of
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isoquinolinium salts is a wellꢀestablished method,
and in a first trial, the
hexafluorophosphate salt (–)ꢀ8b was stirred in ethanol at ambient temperature in the
1
presence of three fold excess of sodium borohydride. Unfortunately, the H NMR
analysis of the reaction mixture revealed the presence of the intermediary 1,2ꢀ
dihydroisoquinoline as the major compound and varying amounts of unidentified
products. In a second trial, the same experiment was carried out in the presence of 2
equiv of acetic acid to afford the expected THIQ (+)ꢀ6a in yields ranging from 50%
and 65%.
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a
Scheme 2. Syntheses of THIQs (+)-6a,b
MeO
MeO
MeO
MeO
(
a)
HN
Ph
Me
(–)ꢀ5
ref. 26
N
Ph
Me
0
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(+)ꢀ6b, 93%
Cl
NO2
(
b)
NO2
+
N
N
Cl
, 78%
NO2
NO2
Ph
7
(c)
(e)
N
Ph
N
H N
2
Ph
Me
X
Me
Me
+)ꢀ6a, 80%
8
a, X = Cl–
–)-8b, X = PF6–, 70%
(
(
d)
(
a
Reagents and conditions: (a) HCO H, (CH O) , 50 °C, 12 h; (b) isoquinoline, 1ꢀchloroꢀ2,4ꢀ
2
2
n
2 2 2
dinitrobenzene, 60 °C, 2 h, then acetone, reflux, 2 h; (c) (–)ꢀαꢀPEA, Et NH, CH Cl , rt, 48 h; (d) 37%
HPF ; (e) NaBH CN, THF, rt, 12 h.
6
3
1
Unfortunately, close examination of the H NMR spectra of derivatives still revealed
the presence of oligomeric compounds which could not be removed by column
chromatography. Finally, the best yields and reaction rates were obtained when the
reduction was performed in the presence of 2 equiv of NaBH CN to afford cleanly
3
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and reproducibly the THIQ (+)ꢀ6a {[α]
D 3
= +9.2 (c 0.5, CHCl )} in 80% yield.
Analytical study of THIQs (+)-6a,b. The electrochemical behavior of THIQ (+)ꢀ6a,b
was studied by cyclic voltammetry and details are reported in table 1. The
polarization curves were recorded at a vitreous carbon electrode at a scan rate of 50
–1
mVs on a 20 mM solution of THIQs (+)ꢀ6a,b in methanol containing LiClO
as the supporting electrolyte and NaCN as the trapping agent. The first
voltammogram was recorded on a 20 mM solution of THIQ (+)ꢀ6a ( = 0, table 1), and
the feature of primary interest in the voltammogram is the presence of a wellꢀdefined
irreversible bielectronic system which was recorded at E = +1.0 V.
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(0.1 M)
γ
p
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Table 1. (Top) Redox and proton transfer options for aminium radical cations A and synthesis
of α-amino nitrile 2a. (Bottom) Cyclic Voltammograms of THIQ (+)-6a in the absence (γ = 0) and
a
in the presence (γ = 1–3) of NaCN
R1
R1
R2
+
1.0 V vs ECS
N
Ph
Me
N
Ph
R2
MeOH/LiClO , NaCN (2 equiv)
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CN Me
(
+)ꢀ6a,b
2
a,b
CN•
CN–
redox
–
e
CN–
CN– HCN
R
1
R
1
R1
R2
–e
N
Ph
Me
N
Ph
N
Ph
Me
R2
R2
•
H1
Me
C
A
B
0
p
0
p
0
Entry
no
E (V)
γ
= 1 (i /i )
γ
= 2 (i /i )
γ
= 3 (i /i )
p
p
p
p
p
1
2
(+)ꢀ6a
(+)ꢀ6b
+1.00
+0.90
1.42
1.90
1.90
1.72
2.50
3.00
a
–1
MeOH/LiClO
4
•3H
2
O (0.1 M), glassy carbon electrode, v = 0.05 V s :
γ = 0 : THIQ (+)ꢀ6a (20 mM)
alone;
γ
= 1 plus NaCN (20 mM);
γ
= 2: plus NaCN (40 mM); = 3: plus NaCN (60 mM).
γ
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The addition of incremental amounts of sodium cyanide (up to 2 equiv) to the
previous solution caused an increase of the anodic current which is no longer under
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diffusion control. The effect of cyanide on the voltammetric profile of (+)ꢀ6a is
attributed to the presence of a typical catalytic current due to the return of the
aminium radical cation
A to its neutral form which occurred during the homogeneous
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redox process (table 1, top) in which the cyanide anion is now oxidized at a lower
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potential than that required for its direct oxidation at the electrode surface. The
0
0
p p p p
magnitude of such process is given by the value of the i /i ratio (where i and i
represent the anodic currents in the presence and in the absence of sodium cyanide,
0
respectively). At low concentrations of sodium cyanide (up to 40 mM) the
i
p
/
i
p
ratio
turned to be 1.90 indicating that the redox process predominantly occurred. In
0
contrast, further addition of sodium cyanide did not modify the
evidence that acid properties of radical cation
result, deprotonation at C1 yields the neutral aminyl radical
oxidized at the electrode surface to form the stable iminium cation
i
p
/
i
p
ratio providing
A
dominate at this concentration. As a
which is immediately
B
32
C
.
A similar behavior was observed for THIQ (+)ꢀ6b (Table 1, entry 2). The
0
values of the p
i
/
ip ratios indicate that electron donating substituents on the aromatic
ring did not significantly modified the redox properties of our substrates, and it was
also concluded that the initial electron transfer involved the amine moiety.
Anodic cyanation of THIQs (+)-6a,b. The electrolysis of THIQ (+)ꢀ6a was carried
out at a vitreous carbon electrode in an undivided batch cell at a controlled potential
of +1.0 V in the presence of 2.5 molar excess of sodium cyanide and 0.5 equiv of
acetic acid to balance the excess of base that was produced at the cathode surface.
After the consumption of 2.1 F per mole of substrate, the cyclic voltammogram
recorded on the resulting solution showed the disappearance of the first oxidation
peak, and aqueous workꢀup and filtration of the crude reaction mixture on a silica
column afforded
αꢀamino nitrile 2a which was obtained in 81% yield as a mixture
(60/40) of diastereoisomers. Slow crystallization of this mixture in a diethyl
ether/petroleum ether biphasic system afforded single crystals which were found to
be suitable for an Xꢀray diffraction study, and from the ORTEP view of (+)ꢀ2a (Figure
S 13 in the Supporting Information) we were able to determine the absolute
configuration of the C1 carbon atom of the major diastereoisomer as
R.
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The electrolysis of (+)ꢀ6b was carried out under conditions similar to those
used for 6a. After workꢀup, αꢀamino nitrile (+)ꢀ2b was obtained as a colorless powder
in 70% yield after a rapid crystallization of the crude reaction mixture in ethanol.
Interestingly, a slow crystallization of this powder in the same solvent afforded a
single crystal which was suitable for an Xꢀray diffraction study. The ORTEP view is
shown in Figure S 23 in the Supporting Information. As the absolute configuration of
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the exocyclic benzylic carbon is known to be
S, the R absolute configuration of the
newly created stereogenic center at C1 is simply deduced from examination of the
structure. In addition, the determination of the Flack parameters values [–0.03 (6)]
calculated from the Friedel pairs reflection for each structure confirmed the absolute
configuration of (+)ꢀ2b in the solid state.
Syntheses of 1-alkyl-THIQs 1a-i. With the required αꢀamino nitriles in hand,
we set to synthesize 1ꢀalkylꢀTHIQs 1a–e displaying an alkyl chain with an increasing
length, and the results are collected in Table 2. The deprotonation sequence was
carried out on a frozen (–80 °C) THF solution of a diastereoisomeric (60/40) mixture
of
αꢀamino nitrile 2a by the slow addition of 1.5 equiv of LDA (prepared from
diisopropylamine and 2.5 M of BuLi) upon which the resulting solution turned rapidly
deep red. The solution was warmed up to –20 °C over a 2 h period, before being
cooled down to –80 °C. The commercially available alkyl iodides were added at that
temperature on the anion solution to afford the unstable quaternary αꢀamino nitriles D
which were used in the next step without further purification. To control the
diastereoselectivity of the hydride incorporation, the reductive decyanation was best
4
achieved when an excess (4 equiv) of NaBH was introduced onto a solution of D in
ethanol at –20 °C. Workꢀup and a filtration over a silica column afforded THIQs 1a–e
in yields ranging from 72% to 40% (Table 2, entries 1–5). Upon comparing entries 3
and 4, one sees that the size of the alkyl chain has an influence on the yield. Entry 5,
clearly showed the effect of the length of the alkyl chain, and a prolonged stirring was
however required to complete the reaction with 1ꢀiodoundecane. It is also worth
mentioning that the parent THIQ (+)ꢀ6b, which resulted from the reductive
decyanation of unreacted
αꢀamino nitrile 2b, was recovered in 20% yield. The
stereoselectivity of the reductive decyanation process has been determined from the
1
careful examination of the H NMR spectra. For compound (–)ꢀ1d, a doublet of
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
doublet (
J
= 8.3, 4.2 Hz, 0.88 H) attributable to the 3ꢀHb proton of the major
diastereoisomer was recorded at
δ = 3.50, whereas the similar system was recorded
at = 3.95 for 3ꢀHb proton of the minor diastereoisomer indicating that these two
δ
derivatives are present in a 90:10 ratio. Comparing entries 1–5 also revealed that the
length of the alkyl chain has little effect on the stereochemical outcome of the
reductive decyanation procedure. To extend the scope of our methodology, we also
decided to evaluate the reactivity of benzyl bromides displaying one or two methoxy
substituents on the aromatic ring. Thus, the treatment of the anion solution of 2a with
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1ꢀ(bromomethyl)ꢀ4ꢀmethoxybenzene afforded the corresponding bifunctional
αꢀamino
nitrile which was reduced as above to provide the THIQ (+)ꢀ1f in 75% yield and in a
D
95:5 dr which could be improved to 99:1 dr by a slow crystallization in ethanol. To our
satisfaction, an Xꢀray study performed on one of these crystals revealed the
stereochemical outcome of the decyanation process. The ORTEP view (Figure S 43
in the SI) clearly shows that the newly created stereogenic center at C1 was
indicating that incorporation of the hydride had occurred on the least hindered Re
face or the intermediary iminium . From Table 2, it is also seen that when 4ꢀ
(bromomethyl)ꢀ1,2ꢀdimethoxybenzene was selected as the electrophile, the THIQ
S
E
33
(+)ꢀ1g was obtained in 70% yield and in a 99:1 dr after crystallization. As an
extension of the previous reaction sequence, we sought to introduce a three carbon
chain tethered by a potential cyclizing group with the aim of synthesizing
pyrroloisoquinoline (–)ꢀ4. Alkylation of the anion solution of 2a with 2ꢀ(2ꢀ
iodopropoxy)ꢀtetrahydropyran or 2ꢀ(2ꢀiodoethyl)ꢀ1,3ꢀdioxolane as the alkylating
1
agents, afforded the THIQ (–)ꢀ1h and (–)ꢀ1i, respectively. Analyses of the H and the
13
C NMR spectrum were straightforward. For example, in the case of THIQ (–)ꢀ1i, the
CH proton of the
signal ( = 4.6 Hz) at
recorded at
O
,O
’ꢀacetal protecting group (J = 4.6 Hz) resonated as a triplet
J
δ
= 4.71 in the major diastereoisomer. The same signal was
S,S
δ
= 4.92 and comparison of the relative integration of these two
characteristic protons showed that reductive decyanation occurred in a 97:3 dr. The
nature of the iminium species has an effect on the stereochemical outcome of the
reductive decyanation, as the best dr’s were obtained in the presence of oxygenated
chains at C1 as shown by entries 6–9. Gratifyingly, THIQs (–)ꢀ1h,i could be obtained
as sole products (99:1 dr’s) after a careful filtration over silica column.
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a
Table 2. Syntheses of THIQs 1a–i
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry
no.
(–)ꢀ1a
R1
yield (%)
72
dr
1
2
3
4
CH
3
90:10
90:10
88:12
90:10
85:15
95:5
(–)ꢀ1b
C
3
H
7
73
(–)ꢀ1c
C
5
H
11
15
71
(–)ꢀ1d
C
7
H
60
b
5
(–)ꢀ1e
C
11
H
23
40
c
6
(+)ꢀ1f (Xꢀray)
(+)ꢀ1g (Xꢀray)
(–)ꢀ1h
4ꢀ(MeO)ꢀPhꢀCH
3,4ꢀ(MeO) ꢀPhꢀCH
(CH ) ꢀOꢀTHP
2
75
c
7
2
2
70
95:5
8
9
70
95:5
2
3
(–)ꢀ1i
(CH
2
)
2
ꢀ1,3ꢀdioxolane
70
97:3
a
Reagents and conditions: Procedure A: (a) LDA, THF, –80 °C to 0 °C, 2 h, then RX, –80 °C to –10
b
c
°
4
C; (b) NaBH , EtOH, 20 °C, 12 h. THIQ (+)ꢀ6b was recovered in 20% yield. THIQs (+)ꢀ1f,g were
obtained as single diastereoisomers after a slow crystallization in ethanol.
Synthesis of N-Boc THIQs (+)-10a–g. Benzyl groups are commonly
employed to protect secondary amines and as shown below, they proved to be useful
when a substrate had to be subjected to basic conditions. In contrast to catalytic
hydrogenolysis of simple benzylamines which are generally carried out in the
presence of a low Pd/C catalyst loading, debenzylation of substrates containing the
more sterically demanding
elevated hydrogen pressure and catalyst loading. Examining the structure of THIQs
a–g, one can see that a nonꢀselective cleavage of the endocyclic C1–N2 bond
αꢀPEA group are generally performed under more
1
could occur in competition with removal of the chiral auxiliary. The first experiment
was carried out with 10% Pd/C (20% in mass) under a hydrogen pressure of 5 bars
and with THIQ (–)ꢀ1b as the substrate. After treatment, the expected THIQ (–)ꢀ9b
was obtained in a low 10% yield accompanied by unreacted starting material. It was
also found in a second experiment that higher catalyst loading (up to 30%) resulted in
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a nonꢀselective cleavage of the C8a–C1 bond. Finally, the best yields and reaction
rates were obtained upon a 48 h stirring of THIQs 1a–g in ethanol under an H
2
atmosphere of 5 bars in the presence of Pearlman’s catalyst (20% in mass).
a
Table 3. Syntheses of N-Boc-THIQs (+)-10a–g
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
entry
no.
R
1
yield (%)
80
entry
10
no.
yield (%)
80
1
2
3
4
5
8
9
(–)ꢀ9a
(–)ꢀ9b
(–)ꢀ9c
(–)ꢀ9d
(–)ꢀ9e
(–)ꢀ9f
(–)ꢀ9g
CH
3
(+)ꢀ10a
(+)ꢀ10b
(+)ꢀ10c
(+)ꢀ10d
(+)ꢀ10e
(+)ꢀ10f
(+)ꢀ10g
C H
3
73
11
85
7
C
C
5
7
H
H
11
15
70
12
75
80
13
73
C H
23
75
14
75
11
4ꢀ(MeO)ꢀPhꢀCH
2
70
18
80
3,4ꢀ(MeO) ꢀPhꢀCH
2
2
80
19
78
a
Reagents and conditions: Procedure B: (a) 20% Pd(OH) /C, H (5 bar), EtOH, 48 h. Procedure C: (b)
2
2
2
(Boc) O, Hünig’s base, acetonitrile, reflux, 4 h, then NaOH 4 M/THF, rt, 2 h.
We could observe clean reductions with yields ranging from 73% to 80% (Table 3)
and to prevent oxidation with ambient air, these derivatives were converted into the
corresponding
N
2
ꢀBocꢀTHIQs (+)ꢀ10a–g by treatment with Boc O in the presence of
1
Hünig’s base in refluxing acetonitrile. In all cases, H NMR analysis revealed the
presence of two rotamers which strongly affect the interpretation of the spectra. For
example, in the spectrum of (+)ꢀ10g in CDCl
3
at 296 K, the signals for the rotamers of
= 5.14 and = 5.33 and were found to
the H1 proton exhibit resonance signals at
exist in a 65:35 ratio.
δ
δ
Synthesis of pyrroloisoquinoline (–)-3 and tetrahydroberberine (–)-4
From the requisite THIQ (–)ꢀ1h in hand, we first turned our attention to the synthesis
of pyrroloisoquinoline (–)ꢀ . Previous studies from this laboratory and others, showed
.
3
that the third pyrrolidine ring could be constructed by the intramolecular displacement
of a terminal chloride leaving group by the deprotected amine. As shown below, the
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synthesis of the requisite amino alcohol (–)ꢀ9h (scheme 3) was carried out in a three
step procedure. The acid catalyzed deprotection of OꢀTHP protected THIQ (–)ꢀ1h
was carried out without event by stirring it at 20 °C in a 1:1 mixture of THF and 2 N
22
D
HCl. The amino alcohol (–)ꢀ1j was obtained in 94% yield as an oily residue {[α] –
1
3
5
7 (c 1.0, CHCl
resonance line in the region
as a single diastereoisomer. Removal of the chiral auxiliary was initiated with
hydrogenolysis of the ꢀPEA group using Pd(OH) as the catalyst under H
3
} and its C NMR, well resolved, displayed a set of 8 independent
10
11
12
13
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15
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21
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23
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29
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32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
δ
= 20–35, providing evidence that this compound exists
N
ꢀα
2
2
atmosphere, a procedure that proved inefficient in that case. The starting material
was recovered in nearly quantitative yield and a prolonged stirring (up to 72 h) did not
modified the conversion. To circumvent these drawbacks, we utilized a protocol
34
described by Polniaszek. Thus, the catalyst (10% Pd/C) was pretreated under an
atmosphere of 6 bar in a 10:2 mixture of ethanol and 10 M HCl for 12 h, prior to
the addition of amino alcohol (–)ꢀ1j. The resulting solution was stirred for an
additional 72 h period under the same H pressure to afford the expected (–)ꢀ9h in
5% yield as a viscous oily residue after column chromatography. Chlorination of the
pendant alcohol was accomplished by refluxing (–)ꢀ9h in CH Cl in the presence of a
H
2
2
7
2
2
35
twoꢀfold excess of SOCl
intermediary hydrochloride salt was not isolated but was stirred in a biphasic system
(Et O/2M NaOH) to afford (–)ꢀ in 81% yield. The spectroscopic data, the magnitude
2
according to the protocol described by Xu. The
3
2
22
and the sign of the optical rotation of our sample {[
D
α] –106 (c 0.5, MeOH)}
36
matched in all aspects with those previously reported in the literature.
To complement the previous synthetic efforts, an alternate procedure for the
formation of the pyrrolidine ring was sought. This approach is based on the formation
of an unstable iminium ion which could be prepared from THIQ (–)ꢀ9i through the
condensation of the terminal aldehyde group and the deprotected N2. In this
sequence, the hydrogenolysis of THIQ (–)ꢀ1i should be carried out first under non
acidic conditions, and we found that Pearlman’s catalyst was the reactant of choice.
Following the previous procedure, THIQ (–)ꢀ9i was obtained in a satisfactorily 65%
yield as an oily residue which should be stored at –20 °C to avoid aerial
37
carbonatation. Deprotection of the
O,O’ꢀdioxolane moiety was carried out by stirring
(–)ꢀ9i in a degassed mixture of THF and 10% HCl over a 24 h period and after the
removal of the organic solvent, the pH of the remaining solution was raised up to 4.5
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
upon the addition of solid AcONa. Then, the resulting emerald green solution was
treated with an excess of sodium cyanide, causing the precipitation of
αꢀamino nitrile
11
as a 1:1 mixture of diastereoisomers. For our purposes, this mixture was
dissolved in ethanol and treated with NaBH for removal of the cyanide group.
4
Because it appeared difficult to remove it under standard conditions, the crude
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reaction mixture was refluxed for an additional three hours period to afforded (–)ꢀ
an overall 60% yield from (–)ꢀ9i
3
in
.
a
Scheme 3. Syntheses of pyrroloisoquinoline (–)-3 and tetrahydroberberine (–)-4
a
Reagents and conditions: (a) THF/HCl 2 N, 1:1, rt, 12 h; (b) 10% Pd/C, EtOH/ HCl 10 N, 10:2, H
2
(6
bar); then, (–)ꢀ1h, H (6 bar), rt, 72 h; (c) SOCl , reflux, 3 h; (d) 20% Pd(OH) /C, H (5 bar), EtOH, 48
2
2
2
2
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4
h; (e) THF/HCl 2 N, rt, 24 h; then AcONa, pH = 4.5; then NaCN, rt, 2 h; (f) NaBH , EtOH, 24 h, rt; then
reflux, 3 h; (g) HCO H/35% HCHO, reflux, 2 h.
2
22
The optical rotation of this sample {[
α]
–98 (c 0.5, MeOH)} was consistent with that
D
reported above, confirming the chiral conservation in both the synthetic approaches.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To extent this approach further, we performed the synthesis of the tetracyclic
compound (–)ꢀ
4
by refluxing its precursor (+)ꢀ9g in a mixture of 35% formalin and
was
), mp 146–148 °C)} in 72% yield after
column chromatography. A further Xꢀray study which was performed on a single
crystal of (–)ꢀ confirmed the proposed structure.
formic acid for 2 h. After an aqueous workꢀup, the tetrahydroberberine (–)ꢀ
4
22
D 3
obtained as a solid {[α] –360 (c 0.5, CHCl
38
4
Stereoselective syntheses of THIQs alkaloids. These encouraging results
prompted us to expand the scope of our study to the synthesis of naturally occurring
39,40
THIQs such as (+)ꢀsalsolidine or (–)ꢀnorlaudanosine.
preparation of (+)ꢀsalsolidine involved the alkylation of
The synthetic scheme for
αꢀamino nitrile (–)ꢀ2b which
was prepared from THIQ (–)ꢀ6b by anodic cyanation. Thus, treatment of (–)ꢀ2b
according to protocol A with iodomethane as the alkylating agent (Scheme 4),
afforded THIQ (+)ꢀ1k (85%) in a 85:15 dr which was determined from examination of
1
the H NMR spectrum in C
6
D
6
. Similarly, the preparation of THIQ (–)ꢀ1l, the
advanced precursor of (–)ꢀnorlaudanosine, proceeded in 90% yield (90:10 dr) from
the alkylation–reduction sequence of enantiomeric ꢀamino nitrile (+)ꢀ2b with 4ꢀ
bromomethyl)ꢀ1,2ꢀdimethoxybenzene as the electrophile. Unfortunately, the
diastereomeric ratio of these two precursors could not be increased by fractionate
crystallization and as shown in scheme 4, selective removal of the ꢀPEA group by
hydrogenolysis afforded enantiomerically enriched (+)ꢀsalsolidine (85:15 er) and (–)ꢀ
norlaudanosine (90:10 er) in 64% and 81% overall yields from enantiomeric ꢀamino
α
(
Nꢀα
α
nitriles 2b, respectively. At this point, it should also be noted that neither variation of
the temperature nor modification of the hydride source could improve the
stereoselectivity of the reductive decyanation. In literature, the optical resolution of
THIQ racemates can be traced back to 1938, when Späth reported the
41
cocrystallization of salsolidine with chiral tartaric acid. This approach is simple and
effective and prompted us to screen a series of carboxylic acids that would hopefully
afford the expected alkaloids as single enantiomers. After several experiments, it was
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
found that addition of (–)ꢀDBTA to an enantioenriched mixture of (+)ꢀsalsolidine
(85:15 er) afforded the corresponding diastereoisomeric salts in nearly quantitative
yield.
a
Scheme 4. Stereoselective synthesis of (+)-salsolidine and (–)-norlaudanosine
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Reagents and conditions: Procedure A: (a) LDA, THF, –80 °C to 0 °C, 2 h, then CH
C, then: NaBH , EtOH, 20 °C, 12 h. (b) 10% Pd/C, EtOH/ 10% HCl (10:2), H (7 bar), 48 h. (c)
Procedure A but with 4ꢀ(bromomethyl)ꢀ1,2ꢀdimethoxybenzene. (d) Procedure B: 20% Pd(OH) /C, H (5
3
I, –80 °C to –10
°
4
2
2
2
bar), EtOH, 48 h.
Gratifyingly, a single crystallization of this mixture in ethanol afforded the tartaric salt
1
(
–)ꢀ12 in 78% yield and the H NMR attested of the 1:1 stoichiometry of this complex
2
(Scheme 5). A base treatment (Et O/10% NaOH) of this salt, afforded enantiopure
(+)ꢀsalsolidine which was obtained as an oil. The optical rotation of our synthetic
22
sample {[
α]
D
+46.7 (
c
3
1, CHCl )} matched the values reported in the literature
2
2
39h
{[
α
]
D
+51 (
c
1, EtOH)}.
The access to enantiopure (–)ꢀnorlaudanosine was
ꢀacetylꢀ ꢀleucine as the
resolving agent according to the protocol formerly reported by Corrodi and
carried out to the similar crystallization process but with (–)ꢀ
N
L
42
Hardegger. The expected leucinate salt (–)ꢀ13 was obtained in 78% yield (99:1 dr)
and a basic treatment of this salt afforded (–)ꢀnorlaudanosine in a 99:1 er.
Determination of enantiomeric ratios of THIQ alkaloids by proton and carbon
NMR spectroscopy. We encountered problems with baseline return during
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chromatographic separation of THIQs enantiomers and therefore turned to NMR to
determine the optical purity of our samples. In contrast to chiral derivatizing agents
which rely on bond formation with the substrate, chiral solvating agents (CSAs) do
not require chemical manipulations thus facilitating the sample recovery. Previous
studies from this laboratory and others, have shown that CSAs which are able to bind
to enantiomers through Brønsted–Lowry acid/base interactions could form
diastereoisomeric salts which could be differentiated by NMR spectroscopy. Thus, we
10
11
12
13
14
15
16
17
18
19
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21
22
23
24
25
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50
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59
60
turned to the utilization (R)ꢀ(+)ꢀtertꢀbutylphosphinothioic acid (+)ꢀ14 as CSA to
determine the enantiomeric ratios of our samples of (+)ꢀsalsolidine and (–)ꢀ
norlaudanosine by proton and carbon spectroscopy (Scheme 6). The addition of 1.5
equiv of (+)ꢀ14 to an enantioenriched mixture (85:15 er) of (+)ꢀsalsolidine dissolved in
6 6 P P
C D resulted in the formation of the thiophosphinic salts (R,R )ꢀ15 and (S,R )ꢀ15.
Scheme 5. Approaches for obtaining enantiopure (+)-salsolidine and (–)-norlaudanosine from
enantiomerically enriched mixtures
As expected and observed, the C1ꢀMe resonance signal in the proton NMR
spectrum of the major diastereoisomer (R,RP)ꢀ15 resonated as a doublet signal (J =
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2
2
2
2
2
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6.7 Hz) at
δ
= 1.72, whereas the C1ꢀMe group in the minor diastereoisomer exhibited
a similar doublet signal at
δ = 1.66. The magnitude of the ꢀδ (0.06) allowed the
enantiomeric ratio to be determined from the further integration of these two signals
which proved to be 85:15 dr. This result also indicated that no racemization occurred
during the removal of the chiral auxiliary in the parent THIQ (+)ꢀ1k, and when a
similar experiment was carried out on optically pure (+)ꢀsalsolidine, a single doublet
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
0
1
2
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
was observed at
δ = 1.72, indicating that our synthetic alkaloid had a >98:2 er. As
expected, an analogous experiment performed with enantioenriched (–)ꢀ
norlaudanosine (90:10 er) provided a well resolved spectrum in which the Hꢀ6’ proton
resonated as a characteristic doublet of doublet (
J = 8.1, 1.7 Hz) at δ = 6.82 in the
major complex ( )ꢀ16
S
,R
P
.
Scheme 6. Determination of the enantiomeric ratios of (+)-salsolidine and (–)-norlaudanosine
by proton NMR spectroscopy
a
a
6 6
Reagents and conditions: (R)ꢀ(+)ꢀtertꢀbutylphenylphosphanylthioic acid, (+)ꢀ14, C D .
Conversely, the Hꢀ6’ proton signal resonated downfield at
complex ( )ꢀ16 indicating that both molecules could be efficiently discriminated in
this way. Finally, when a similar experiment was carried out on optically pure (–)ꢀ
norlaudanosine, a single resonance signal ascertained to the Hꢀ6’ proton in ( )ꢀ16
was recorded at = 6.82, providing the final proof that our sample was
enantiomerically pure.
δ = 6.90 in the minor
R,R
P
S,R
P
δ
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Synthesis of (+)-carnegine and (–)-xylopinine. Finally, methylation of the free
nitrogen atom of (+)ꢀsalsolidine was carried out according to the protocol first
43
described by Borch (Scheme 7).
Thus, addition of an excess of sodium
cyanoborohydride on a solution of (+)ꢀsalsolidine (99:1 er) and aqueous
formaldehyde in acetonitrile at pH = 7, afforded (+)ꢀcarnegine in 73 % yield after
workꢀup and purification of the crude reaction mixture on a silica gel column. The
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2
2
specific optical rotation of our sample of (+)ꢀcarnegine proved to be [
α
]
D
+18 (
c
1.0,
+23.5 (
.5, EtOH)}. The synthesis of (–)ꢀxylopinine, the prototypical member of the
22
D
EtOH), which is in close agreement to that reported in the literature {[
α
]
c
44
1
tetrahydroberberines which was isolated from Xylopia Discreta, seemed to be also an
45
interesting possibility. This, can be cleanly achieved by refluxing (–)ꢀnorlaudanosine
(displaced from its leucinate salt (–)ꢀ13) for two hours in a mixture of 35%
formaldehyde in formic acid.
a
Scheme 7. Synthesis of (+)-carnegine and (–)-xylopinine
a
Reagents and conditions: (a) aq. HCHO (35%), NaBH
3 3 2
CN, pH = 7, CH CN, 15 min; (b) HCO H/aq.
HCHO (35%), reflux, 2 h.
Basic treatment and purification of the crude reaction mixture by silica gel
chromatography, afforded (–)ꢀxylopinine as a white solid in a combined 90% yield
from (+)ꢀ12 with specific optical rotation and spectral data identical to that reported
for the natural product. Additionally, an Xꢀray study which was carried out on a single
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crystal of (–)ꢀxylopinine confirmed the proposed structure and provided the final proof
that the PictetꢀSpengler type cyclization process occurred regioselectively to form the
C8–C8a bond, the soꢀcalled “berberine” bridge.
Conclusion
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0
In summary, we have found that LDA is able to deprotonate an isoquinoline based
chiral non racemic
condensed on a set of alkyl halides and the intermediary quaternary
thus obtained are submitted to a reductive decyanation procedure to yield a series of
αꢀamino nitrile in THF. The resulting
αꢀamino cyano carbanion is
α
ꢀamino nitriles
1
ꢀalkylꢀTHIQs in excellent yields with diatereoisomeric ratios ranging from 85:15 to
7:3. The same chemistry was applied successfully to the synthesis of THIQs (+)ꢀ
9
salsolidine and (–)ꢀnorlaudanosine which was cyclized into (–)ꢀxylopinine whose Xꢀ
ray crystallography study was reported for the first time in the literature. Our efforts
are currently directed toward the application of this strategy to the asymmetric
synthesis of more complex molecule containing a THIQ nucleus. These results will be
reported on due course.
Experimental section
General Techniques: Purification by column chromatography was performed
with 70–230 mesh silica gel. TLC analyses were carried out on alumina sheets
1
precoated with silica gel 60 F254;
R
f
values are given for guidance. The H NMR
spectra were recorded with a 500 MHz, a 400 MHz or a 300 MHz spectrometer. The
13
C NMR spectra were recorded with a 125 MHz, a 100 MHz or a 75 MHz
spectrometer. Positiveꢀion mass spectra were recorded on an orthogonal
acceleration quadrupole timeꢀofꢀflight mass spectrometer equipped with a standard
electrospray probe. Melting points were measured on a Kofler apparatus, the values
reported in °C, and were uncorrected. Optical rotations were recorded at 20 °C in a 1
dm cell. For airꢀsensitive reactions, the glassware was ovenꢀdried (90 °C) for 24 h
and cooled under a stream of argon before use. All commercially available reagents
were used as supplied and THF was distilled over sodium benzophenone ketyl.
Diisopropylamine was distilled from solid potassium hydroxide.
Electrochemical techniques. Cyclic voltammetry experiments were carried
out on a potentiostat using a threeꢀelectrode device with a glassy carbon (GCE,
diameter = 2 mm) as the working electrode, a saturated calomel electrode (SCE) as
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the reference and a platinum wire as the auxiliary electrode. The experiments were
–1
carried out in methanol containing LiClO
4 2
•3H O (0.1 mol L ) as the supporting
electrolyte. Preparative electrolysis were carried out at a controlled potential in a
46
single compartment cell which was described previously. The solution was stirred
with a magnetic stirring bar and the electrolysis was stopped after the consumption of
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60
2
.1 F/mole.
4
7
2-(2,4-dinitro-phenyl)-isoquinolinium chloride, 7. A 200ꢀmL Schlenk tube fitted
with a magnetic stirring bar was successively charged with 10 mL (11.00 g, 85.09
mmol) of isoquinoline and 17.10 g (84.42 mmol) of finely powdered 1ꢀchloroꢀ2,4ꢀ
dinitrobenzene. The resulting suspension was stirred vigorously and heated at 60 °C
for 10 minutes. The resulting orange solid paste was warmed at that temperature for
an additional 1 h and 5 mL of acetone were added to the reaction mixture. The
resulting suspension was refluxed for 6 h and the solid was filtered over a sintered
glass funnel and was taken up with a minimum of acetone to afford 21.80 g (78%) of
1
the isoquinolinium chloride
00 MHz) = 8.18 (td, = 7.2, 1.1 Hz, 1 H), 8.45 (td,
8.0 Hz, 1 H), 8.63 (d, = 8.7 Hz, 1 H), 8.69 (d, = 8.2 Hz, 1 H), 8.90 (d,
1 H), 9.04 (dd, = 8.6, 2.5 Hz, 1 H), 9.15 (d, = 2.5 Hz, 1 H), 9.19 (dd,
Hz, 1 H), 10.77 (s, 1 H). C NMR (DMSOꢀd , 100 MHz) = 121.5 (t), 125.3 (t), 126.7
q), 127.6 (t), 130.2 (t), 131.6 (t), 131.8 (t), 132.2 (t), 135.4 (t), 137.9 (q), 138.8 (t),
7
. Orange powder, mp = 200–202 °C. H NMR (DMSOꢀd
6
,
4
δ
J
J
= 7.2, 1.1 Hz, 1 H), 8.56 (d,
= 7.0 Hz,
= 6.8, 2.1
J
=
J
J
J
J
J
J
13
δ
6
(
+
+
139.0 (q), 143.1 (q), 148.9 (q), 152.2 (t). HRMS (ESI , CH OH, C H N O , [M] )
3
15 10
3
4
calcd for 296.0671, found 296.0670. Anal. Calcd for C15
H
10ClN
3
O
4
(331.71): C,
54.31; H, 3.04; N, 12.67. Found: C, 54.15; H, 3.07; N, 12.55.
(
S)-(–)-2-(1-Phenylethyl)-isoquinolinium hexafluorophosphate, (–)-8b, new
compound. A 200 mL Schlenk fitted with a magnetic stirring bar was successively
charged with 100 mL of CH Cl , 5.0 g (15.07 mmol) of Zincke salt , 1.87 mL (1.32 g,
18.07 mmol, 1.2 equiv.) of diethylamine and 2.31 mL (2.22 g, 18.33 mmol, 1.2 equiv.)
of ( )ꢀ(–)ꢀ1ꢀphenylethylamine. The red solution was stirred at 20 °C for 48 h and the
2
2
7
S
solvent was evaporated under reduced pressure to afford a solid gum which was
taken up with 50 mL of water containing 5ꢀ10 drops of a 35% ammonia solution. The
2,4ꢀdinitroaniline was filtered off and the aqueous phase was extracted with 20 mL of
AcOEt (× 3). The combined organic layers were discarded and the isoquinolinium
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chloride (8a) solution was treated for 12 h with 5 mL of a 37% solution of
hexafluorophosphoric acid. The resulting suspension was extracted with 30 mL of
dichloromethane (× 3) and the combined organic phases were washed with water
4
until neutral pH. The organic phases were dried over MgSO and concentrated to
afford 4.03 g (70%) of isoquinolinium hexafluorophosphate salt (–)ꢀ8b as a viscous oil
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22
2 2 D
which solidified upon cooling. Slightly orange solid, mp = 106–108 °C (CH Cl ). [α]
1
=
–78 (
c
1.0, CHCl
3
). H NMR (CDCl
3
, 500 MHz)
δ
= 2.12 (d,
J
= 7.0 Hz, 3 H), 6.17
= 8.1 Hz, 1 H),
= 6.9 Hz, 1 H), 8.46 (d,
= 20.3 (p), 71.1 (t), 126.9 (t)
(q,
J
= 7.0 Hz, 1 H), 7.26–7.39 (m, 3 H), 7.48–7.50 (m, 2 H), 7.86 (t,
J
8
.02–8.08 (m, 2 H), 8.21 (d,
J
= 6.9 Hz, 1 H), 8.35 (d,
J
J =
13
8
.3 Hz, 1 H), 9.81 (s, 1 H). C NMR (CDCl , 125 MHz)
3
δ
127.1 (t), 127.5 (t), 127.8 (q), 129.7 (t), 130.1 (t), 131.2 (t), 131.7 (t), 132.1 (t), 136.3
+
+
(
q), 137.58 (t), 137.6(q), 147.7 (t). HRMS (ESI , CH
3
OH, C17H16N, [M] ) calcd for
234.1283, found 234.1282.
(
S)-(+)-2-(phenylethyl)-1,2,3,4-tetrahydroisoquinoline, (+)-6a, new compound. A
00 mL Schlenk tube fitted with a magnetic stirring bar was charged with 20 mL of
THF and 2.0 g (5.27 mmol) of hexafluorophosphate salt (–)ꢀ8b. Then, NaBH CN
2
3
(0.66 g, 10.50 mmol, 2.0 equiv.) was added by portions to the resulting suspension
and the reaction mixture was stirred under argon for 12 h at 20 °C. The solvent was
removed under reduced pressure and the resulting paste was taken up with 20 mL of
water containing 5 drops of a 35% ammonia solution. The resulting suspension was
extracted with 50 mL of dichloromethane (× 2) and the organic phases were dried
over MgSO and concentrated under reduced pressure to afford a crude oil which
4
was transferred to a chromatographic column (diethyl ether/petroleum ether, 3:7).
The combined fractions were evaporated to afford the THIQ (+)ꢀ6a (1.0 g, 80%) as a
2
2
colorless oil. [
α
]
D
= +9.2 (
, 400 MHz)
.90 (m, 3 H), 3.53 (q, = 6.9 Hz, 1 H), 3.54 (d,
Hz, 1 H), 6.93–6.96 (m, 1 H), 7.02–7.08 (m, 3 H), 7.23 (tt,
c
0.5, CHCl
3
).
R
f
= 0.7 (diethyl ether/petroleum ether, 3:7).
= 6.9 Hz, 3 H), 2.56–2.63 (m, 1 H), 2.73–
= 16.0 Hz, 1 H), 3.79 (d, = 16.0
= 5.3, 2.3 Hz, 1 H), 7.28–
1
H NMR (CDCl
3
δ
= 1.47 (d,
J
2
J
J
J
J
13
7.32 (m, 2 H), 7.34–7.37 (m, 2 H). C NMR (CDCl
3
, 100 MHz)
δ
= 20.1 (p), 29.3 (s),
48.0 (s), 53.5 (s), 64.4 (t), 125.5 (t), 125.9 (t), 126.7 (t), 126.9 (t), 127.5 (t), 128.3 (t),
+
+
1
28.6 (t), 134.6 (q), 135.2 (q), 144.3 (q). HRMS (ESI , CH
3
CN, C17
H
20N, [M + H] )
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calcd for 238.1590, found 238.1590. Anal. Calcd for C17
.07; N, 5.90. Found: C, 86.18; H, 7.94; N, 5.90.
H19N (379.28): C, 86.03; H,
8
(1R,2S)-(+)-2-(1-Phenyl-ethyl)-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile, (+)-
2a, new compound. A 500 mL undivided electrolysis cell equipped with a planar
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®
vitreous carbon electrode (diameter 100 mm, Carbone Lorraine ) and a magnetic
stirrer, was successively charged with 300 mL of methanol, 2.0 g (8.42 mmol) of
THIQ (+)ꢀ6a, 3.0 g of LiClO
0.19 g, 3.32 mmol, 0.4 equiv.) of acetic acid. The working potential was adjusted to
+1.0 V/SCE and after the consumption of 1700 C (2.1 F/mol), the electrolysis was
stopped. Then, 150 mL of water were added to the solution (Caution LiClO may
lead to severe explosions when the material is evaporated to dryness. NaCN was
destroyed by adding an excess of KMnO onto the aqueous phase. Due to the
4
, 0.82 g (16.73 mmol, 2.0 equiv.) of NaCN and 0.19 mL
(
:
4
4
possible release of HCN, the electrolysis should be carried out under a well ventilated
hood) and methanol was evaporated under reduced pressure at +50 °C. The
aqueous phase was extracted with dichloromethane (50 mL × 3) and the combined
organic layers were dried over MgSO and concentrated in vacuo. The crude material
4
was diluted in 10 mL of dichloromethane and poured into a chromatographic column
(30 × 3.5 cm) prepared with 30 g of silica and 3:7 petroleum ether/diethyl ether. The
combined fraction were concentrated to afford αꢀamino nitrile 2a (1.78 g, 81%) as a
mixture (6:4) of diastereoisomers. A further slow crystallization (3 weeks) of this
mixture in a biphasic system (petroleum ether/diethyl ether 5:1) afforded a single
crystal of (+)ꢀ2a whose absolute configuration was determined by Xꢀray diffraction.
22
Colorless plate, mp = 104–106 °C (petroleum ether/diethyl ether). [
α]
D
= +21.5 (
c
2
2
1
.0, C H , 99 (R,S):1 (S,S) dr); [α] = –58.0 (c 1.0, C H , 60 (R,S):40 (S,S) dr). Due
6 6 D 6 6
to a slow epimerization of C1(R) in benzene, the optical rotation of the sample should
1
be recorded within a 5 min period
NMR (C , 400 MHz) = 1.20 (d,
2.42–2.55 (m, 2 H), 2.60–2.66 (m, 1 H), 3.66 (q,
dm, = 7.3 Hz, 1 H), 6.90 (td, = 8.4, 1.5 Hz, 1 H), 6.93–6.99 (m, 2 H), 7.05–7.09 (
m, 1 H), 7.12–7.19 (m, 4 H). C NMR (C D , 400 MHz)
.
R
f
= 0.9 (diethyl ether/petroleum ether, 3:7). H
6
D
6
δ
J
= 6.6 Hz, 3 H), 2.06 (dd,
J = 12.6, 4.2 Hz, 1 H),
J
= 6.6 Hz, 1 H), 4.89 (s, 1 H), 6.75
(
J
J
13
δ
= 21.4 (p), 28.2 (s), 44.9
6
6
(
s), 52.4 (t), 62.3 (t), 116.5 (q), 126.2 (t), 127.0 (t), 127.2 (t), 127.4 (t), 128.0 (t), 128.6
1
(
t), 129.2 (t), 130.3 (q), 134.8 (q), 144.7 (q). H NMR (isomeric mixture, 60 (R,S):40
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(
S,S), C
6
D
6
, 400 MHz)
δ
= 1.18 (d,
J
= 6.6 Hz, 1.8 H); 1.20 (d,
= 16.6, 2.6 Hz, 0.4 H); 2.42–2.66 (m,
= 17.1, 11.6, 6.2 Hz, 0.4 H); 2.98 (ddt, = 11.9, 6.3, 1.6 Hz, 0.4 H);
J = 6.6 Hz, 1.2 H);
2
.06 (dd,
J
= 12.6, 4.2 Hz, 0.6 H); 2.34 (dd, J
2
.2 H); 2.76 (ddd,
J
3.66 (q,
.28 (d,
J
J
= 6.6 Hz, 0.6 H), 3.76 (q, J = 6.6 Hz, 0.4 H); 4.52 (s, 0.4 H); 4.90 (s, 0.6 H);
6
= 8.3 Hz, 0.4 H); 6.71–6.76 (m, 1 H); 6.79 (d,
J
= 3.7 Hz, 0.4 H); 6.88–7.00
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
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7
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7
8
9
0
1
(m, 2.2 H), 7.05–7.10 (m, 1 H); 7.12–7.20 (m, 3.2 H); 7.32–7.36 (m, 0.8 H). H NMR
(
isomeric mixture, 60 (R,S):40 (S,S), CDCl
= 6.6 Hz, 1.2 H), 2.56–2.63 (m, 1 H), 2.77 (td,
.83–2.91 (m, 1.8 H), 3.11 (ddd, = 17.4, 11.6, 6.2 Hz, 0.4 H), 3.47 (dd = 11.9, 6.3
Hz, 0.4 H), 3.73 (q, = 6.6 Hz, 0.6 H), 3.80 (q, = 6.6 Hz, 0.4 H), 4.49 (s, 0.4 H),
.18 (s, 0.6 H), 6.96 (d, = 8.3 Hz, 0.4 H), 7.10–7.40 (m, 8.6 H). C NMR (isomeric
mixture, 60 (R,S):40 (S,S), CDCl , 125 MHz) = 21.7 & 21.8 (p), 28.5 & 28.9 (s),
2.6 & 45.0 (s), 52.6 & 54.1 (t), 61.9 & 62.4 (t), 116.8 & 117.1 (q), 126.3 (t), 126.5 (t),
127.1 (t), 127.2 (t), 127.4 (t, 2 C), 127.5 (t), 127.8 (t), 128.3 (t), 128.4 (t), 128.7 (t),
28.9 (t), 129.1 (t), 129.4 (t), 129.8 & 130.3 (q), 134.5 & 134.9 (q), 143.1 &144.4 (q).
3
, 500 MHz)
δ
= 1.47 (d,
J = 6.6 Hz, 1.8
H), 1.50 (d,
J
J
= 11.9, 4.0 Hz, 0.4 H),
2
J
J
J
13
5
J
δ
3
4
1
+
+
HRMS (ESI , CH
3 18 2
OH, C18H N Na, [M + Na] ) calcd for 285.1368, found 285.1361.
Anal. Calcd for C H N (C H N ): C, 82.41; H, 6.92; N, 10.68. Found: C, 82.47; H,
18
18
2
18 18
2
6
.89; N, 10.38.
(1R,1’S)-(+)-6,7-dimethoxy-2(1-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-1-
carbonitrile, (+)-2b. The synthesis was as reported for (+)ꢀ2a vide supra) but with
.0 (6.72 mmol) of (+)ꢀ( )ꢀ6,7ꢀdimethoxyꢀ2ꢀ(1ꢀphenylethyl)ꢀ1,2,3,4ꢀ
(
2
g
S
tetrahydroisoquinoline (+)ꢀ6b. After the consumption of 1430 C (2.2 F/mol), 100 mL
of water were added to the electrolysis solution. Methanol was evaporated under
reduced pressure and the aqueous phase was extracted twice with 100 mL of diethyl
ether. The combined organic layers were dried over magnesium sulfate and
concentrated. The crude reaction mixture was crystallized in a minimum of boiling
ethanol containing 0.1 g of sodium cyanide to afford 1.58 g (73%) of (+)ꢀ2b as a
22
D 6 6
white solid: mp 163–165 °C; [α] +40 (c 1.0, C D ). Spectral data were reported in
26a
ref. . A single crystal was obtained upon a slow crystallization in ethanol and was
studied by Xꢀray crystallography.
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(1S,1’R)-(–)-6,7-dimethoxy-2(1-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-1-
carbonitrile, (–)-2b. The synthesis was as reported for (+)ꢀ2a but with (–)ꢀ(
R)ꢀ6,7ꢀ
dimethoxyꢀ2ꢀ(1ꢀphenylethyl)ꢀ1,2,3,4ꢀtetrahydroisoquinoline to afford (–)ꢀ2b as a white
22
D 6 6
solid: [α] –38 (c 1.0, C D ).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Procedure A: synthesis of THIQs 1a–i from αꢀamino nitrile 2a.
1
3a
(1S,1’S)-(–)-1-methyl-2-(1-phenylethyl)-1,2,3,4-tetrahydroisoquinoline, (–)-1a.
An oven dried, 200ꢀmL, oneꢀnecked Schlenk tube, fitted with a magnetic stirring bar,
connected to an argon inlet tube was flushed with argon, and was successively
charged with 10 mL of dry THF and 1.6 g (6.10 mmol) of
αꢀamino nitrile 2b as a
60:40 mixture of diastereoisomers. The flask was then cooled to –80 °C and 10 mL of
a LDA solution in dry THF [prepared from 1.20 mL (0.86 g, 8.54 mmol) of
diisopropylamine and 2.90 mL (7.25 mmol, 1.18 equiv.) of butyllithium (2.5 M solution
in hexane)] were slowly added by syringe. The anion solution turned rapidly red and
was allowed to warm to –20 °C over a 2 h period and was then cooled to –80 °C.
Then, 1.71 g (0.75 mL, 12.04 mmol, 2.0 equiv.) of iodomethane was added dropwise
and the reaction mixture was allowed to warm to –20 °C for 3 h. The contents of the
flask were poured into a mixture of 100 mL of diethyl ether and 15 mL of water
containing 0.25 g of NaCN. The organic layer was washed with 10 mL of water, dried
over anhydrous magnesium sulfate, and evaporated under reduced pressure to yield
a crude oily residue which was used in the next step without further purification. The
oily residue was dissolved in 10 mL of ethanol and poured in a 100ꢀmL, oneꢀnecked
flask, equipped with a rubber septum. The flask is cooled to –20 °C, and 0.92 g
4
(24.40 mmol) of NaBH was added in portions. Stirring was continued for 1 h at that
temperature, and the solution was allowed to reach room temperature overnight. The
solvents were evaporated under reduced pressure, and the crude material was
takenꢀup with 20 mL of a 15% ammonia solution and the aqueous layer was
extracted twice with 25 ml of dichloromethane. The combined organic layers were
washed with 25 mL of water, dried over anhydrous sodium sulfate, filtered, and
concentrated on a rotary evaporator. The crude oily residue was diluted with 5 mL of
dichloromethane and poured into a chromatographic column (50 × 2.5 cm), prepared
with 40 g of silica and 1:1 diethyl ether/petroleum ether. The combined fractions were
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
6
evaporated, to afford 1.1 g (72% based on
α
ꢀamino nitrile 2b) of (–)ꢀ1a. Yellow
2
2
viscous oil.
):10 (
R
f
= 0.70 (diethyl ether/petroleum ether, 3:7). [
α
]
D
–21 (
c
1.0, CHCl
) dr, major
= 6.9 Hz, 3
= 6.9 Hz, 1 H),
, 75 MHz) = 19.4 (p),
3
, 90
1
(
S
,
S
R
,S
) dr). H NMR (isomeric mixture, 90 (
S
,S
):10 (
R
,S
diastereoisomer, CDCl
3
, 300 MHz) δ = 1.32 (d, J = 6.9 Hz, 3 H), 1.38 (d, J
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H), 2.47–2.63 (dm, = 14.0 Hz, 1 H), 2.80–3,00 (m, 3 H), 3.75 (q, J
J
1
3
4.06 (q,
J
= 6.9 Hz, 1 H), 6.98–7.38 (m, 9 H). C NMR (CDCl
3
δ
21.3 (p), 26.5 (s), 39.9 (s), 53.6 (t), 59.5 (t), 125.5 (t), 125.7 (t), 126.7 (t), 127.2 (t),
+
127.8 (t), 128.3 (t), 128.9 (t), 134.6 (q), 140.5 (q), 146.6 (q). HRMS (EI , C18
H21N,
+
[
M] ) calcd for 251.1674, found 251.1679. Anal. Calcd for C18
H
21N (251.37): C, 86.01;
H, 8.42; N, 5.57. Found: C, 85.90; H, 8.25; N, 5.87.
(1S,1’S)-(–)-1-propyl-2-(1-phenylethyl)-1,2,3,4-tetrahydroisoquinoline,
(–)-1b,
new compound. The synthesis of THIQ (–)ꢀ1b (1.24 g, 73%, 90:10 dr) was carried
out according to procedure A, but with 1.18 mL (2.06 g, 12.20 mmol, 2.0 equiv.) of 1ꢀ
iodopropane as the alkylating agent. The crude oily residue was diluted with 5 mL of
dichloromethane and poured into a chromatographic column (50 × 2.5 cm), prepared
22
with 40 g of silica and 2:8 diethyl ether/petroleum ether. Orange oil, [
.0, CHCl , 90 ( ):10 ( ) dr).
NMR (isomeric mixture, 90 ( ):10 (
MHz) = 0.80 (t, = 7.4 Hz, 3 H), 1.02–1.15 (m, 1 H), 1.20–1.28 (m, 2 H), 1.38 (d,
= 6.9 Hz, 3 H), 1.70–1.80 (m, 1 H), 2.57 (dt, = 13.0, 3.6 Hz, 1 H), 2.96 (ddd,
6.5, 10.4, 6.9 Hz, 1 H), 3.15–3.22 (m, 2 H), 3.60 (dd, = 8.3, 4.2 Hz, 1 H), 3.75 (q,
α]
= –35 (c
D
1
1
3
S
,
S
R
,S
R
f
= 0.8 (diethyl ether/petroleum ether, 20:80). H
S
,S
R,S) dr, major diastereoisomer, CDCl , 300
3
δ
J
J
=
J
J
J
1
=
J
13
6.9 Hz, 1 H), 6.85–6.90 (m, 1 H), 7.02–7.10 (m, 3 H), 7.20–7.30 (m, 5 H). C NMR
):10 ( ) dr, major diastereoisomer, CDCl , 75 MHz)
4.7 (p), 20.2 (p), 21.5 (s), 24.4 (s), 26.1 (s), 39.7 (s), 58.9 (t), 59.1 (t), 126.0 (t),
(isomeric mixture, 90 (
S
,S
R
,S
3
δ =
1
1
+
27.2 (t), 128.1 (t), 128.7 (t), 129.3 (t), 135.3 (q), 140.0 (q), 146.9 (q). HRMS (ESI ,
+
MeOH, C20
H
26N, [M + H] ) calcd for 280.2065, found 280.2064. Anal. Calcd for
20
C H25N (279.42): C, 85.97; H, 9.02; N, 5.01. Found C, 86.15; H, 9.04; N, 4.94.
(1S,1’S)-(–)-1-pentyl-2-(1-phenylethyl)-1,2,3,4-tetrahydroisoquinoline,
(–)-1c,
new compound. The synthesis of THIQ (–)ꢀ1c (1.33 g, 71%, 88:12 dr) was carried
out according to procedure A, but with 2.46 g, (12.42 mmol, 2.0 equiv.) of 1ꢀ
iodopentane as the alkylating agent. The crude oily residue was diluted with 5 mL of
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dichloromethane and poured into a chromatographic column (50 × 2.5 cm), prepared
22
with 40 g of silica and 2:8 diethyl ether/petroleum ether. Orange oil, [
.5, CHCl , 88 ( ):12 ( ) dr).
NMR (isomeric mixture, 88 ( ):12 (
MHz) = 0.82 (t, = 7.4 Hz, 3 H), 1.02–1.15 (m, 2 H), 1.20–1.28 (m, 3 H), 1.32–1.49
m, 2 H), 1.38 (d, = 6.9 Hz, 3 H), 1.70–1.80 (m, 1 H), 2.49 (dt, = 13.0, 3.6 Hz, 1
H), 2.91 (ddd, = 16.5, 10.4, 6.9 Hz, 1 H), 3.15–3.22 (m, 2 H), 3.50 (dd, = 8.3, 4.2
= 6.9 Hz, 1 H), 6.85–6.89 (m, 1 H), 7.02–7.12 (m, 3 H), 7.18–7.30
):12 ( ) dr, major diastereoisomer,
= 14.1 (p), 21.0 (p), 22.7 (s), 23.9 (s), 26.1 (s), 31.9 (s), 36.8 (s),
39.0 (s), 58.54 (t), 58.58 (t), 126.7 (t), 127.6 (t), 128.1 (t), 128.2 (t), 128.7 (t), 134.8
α]
D
= –30 (
c
1
0
3
S
,S
R
,S
R
f
= 0.8 (diethyl ether/petroleum ether, 2:8). H
S
,S
R,S) dr, major diastereoisomer, CDCl , 400
3
δ
J
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
J
J
J
J
Hz, 1 H), 3.75 (q,
J
13
(
m, 5 H). C NMR (isomeric mixture, 88 (
S
,S
R,S
3
CDCl , 100 MHz) δ
+
+
(
q), 139.6 (q), 146.5 (q). HRMS, (ESI , MeOH, C22
found 308.2373. Anal. Calcd for C22 29N (307.48): C, 85.94; H, 9.51; N, 4.56. Found:
C, 86.19; H, 9.73; N, 4.67.
H30N, [M + H] ) calcd for 308.2378,
H
(1S,1’S)-(–)-1-heptyl-2-(1-phenylethyl)-1,2,3,4-tetrahydroisoquinoline,
(–)-1d,
new compound. The synthesis of THIQ (–)ꢀ1d (1.23 g, 60%, 87:13 dr) was carried
out according to procedure A, but with 2.75 g, (12.20 mmol, 2.0 equiv.) of 1ꢀ
iodoheptane as the alkylating agent. The crude oily residue was diluted with 5 mL of
dichloromethane and poured into a chromatographic column (50 × 2.5 cm), prepared
22
with 40 g of silica and 2:8 diethyl ether/petroleum ether. Orange oil, [
.5, CHCl , 87 ( ):13 ( ) dr).
NMR (isomeric mixture, 87 ( ):13 (
MHz) = 0.86 (t, = 7.4 Hz, 3 H), 1.02–1.15 (m, 2 H), 1.16–1.35 (m, 8 H), 1.37 (d,
6.9 Hz, 3 H), 1.40–1.48 (m, 1 H ), 1.70–1.80 (m, 1 H), 2.50 (dt, = 13.0, 3.6 Hz, 1
H), 2.91 (ddd, = 16.5, 10.4, 6.9 Hz, 1 H), 3.15–3.22 (m, 2 H), 3.52 (dd, = 8.3, 4.2
= 6.9 Hz, 1 H), 6.85–6.89 (m, 1 H), 7.02–7.12 (m, 3 H), 7.18–7.30
):13 ( ) dr, major diastereoisomer,
= 14.1 (p), 20.9 (p), 22.7 (s), 24.0 (s), 26.5 (s), 29.3 (s), 29.7 (s),
α]
D
= –23 (
c
1
0
3
S
,S
R
,S
R
f
= 0.85 (diethyl ether/petroleum ether, 2:8). H
S
,S
3
R,S) dr, major diastereoisomer, CDCl , 400
δ
J
J
=
J
J
J
Hz, 1 H), 3.75 (q,
J
13
(
m, 5 H). C NMR (isomeric mixture, 87 (
S
,S
R,S
CDCl , 100 MHz)
δ
3
31.9 (s), 36.9 (s), 39.1 (s), 58.6 (t), 125.5 (t) 125.6 (t), 126.7 (t), 127.6 (t), 128.1 (t),
+
+
1
28.2 (t), 128.7 (t), 134.8 (q), 139.7 (q), 146.5 (q). HRMS (ESI , MeOH, [M + H] ,
C
24
H
34N) calcd for 336.2685, found 336.2686. Anal. Calcd for C24 33N (335.53): C,
H
85.91; H, 9.91; N, 4.17. Found: C, 85.72; H, 9.84; N, 4.27.
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2
2
2
2
2
2
2
3
3
3
3
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3
3
3
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5
5
6
(
1S,1’S)-(–)-1-undecyl-2-(1-phenylethyl)-1,2,3,4-tetrahydroisoquinoline, (–)-1e,
new compound. The synthesis of THIQ (–)ꢀ1e (0.95 g, 40%, 85:15 dr) was carried
out according to slightly procedure A but with a 4 h stirring at 0 °C) and with 3.44 g
(12.20 mmol, 2.0 equiv.) of 1ꢀiodoundecane as the alkylating agent. THIQ (+)ꢀ6b was
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
recovered in 20% yield after purification of the crude material by column
22
D
chromatography (petroleum ether/diethyl ether, 80:20). Orange oil, [
α]
= –11 (
= 0.8 (petroleum ether/diethyl
):15 ( ) dr, major
= 7.4 Hz, 3 H), 1.02–1.15 (m, 1 H),
= 6.9 Hz, 3 H), 1.40–1.48 (m, 1 H ), 1.70–1.80 (m, 1
= 13.0, 3.6 Hz, 1 H), 2.91 (ddd, = 16.5, 10.4, 6.9 Hz, 1 H), 3.15–3.22
= 8.3, 4.2 Hz, 1 H), 3.75 (q, = 6.9 Hz, 1 H), 6.85–6.89 (m, 1 H),
.02–7.12 (m, 3 H), 7.18–7.30 (m, 5 H). C NMR (isomeric mixture, 85 ( ):15
) dr, major diastereoisomer, CDCl , 100 MHz) = 14.2 (p), 21.0 (p), 22.7 (s),
4.0 (s), 26.5 (s), 29.4 (s), 29.71 (s), 29.75 (s), 32.0 (s), 36.9 (s), 39.1 (s), 58.6 (t),
c
1
.0, CHCl
3
, isomeric mixture, 85 (S,S):15 (R,S) dr). R
f
1
ether, 80:20). H NMR (isomeric mixture, 85 (
S
,S
R,S
diastereoisomer, CDCl
3
, 400 MHz)
δ = 0.88 (t, J
1
.16–1.35 (m, 17 H), 1.37 (d,
J
H), 2.50 (dt,
J
J
(m, 2 H), 3.52 (dd,
J
J
13
7
S,S
(R
,
S
δ
3
2
125.5 (t), 125.6 (t), 126.7 (t), 127.7 (t), 128.1 (t), 128.2 (t), 128.8 (t), 134.9 (q), 139.6
+
+
(
q), 146.5 (q). HRMS (ESI , MeOH, [M + H] ) C28
92.3310. Anal. Calcd for C28 41N (391.64): C, 85.87; H, 10.55; N, 3.58. Found: C,
85.74; H, 10.41; N, 3.66.
H42N calcd for 392.3311, found
3
H
(1S,1’S)-(+)-1-(4-methoxybenzyl)-2-(1-phenylethyl)-1,2,3,4-
13a
tetrahydroisoquinoline, (+)-1f. The synthesis of THIQ (+)ꢀ1f (1.63 g, 75%, 95:5
dr) was carried out according to procedure A, but with 1.84 g, (9.15 mmol, 1.5 equiv.)
of 1ꢀ(bromomethyl)ꢀ4ꢀmethoxybenzene as the alkylating agent. A slow crystallization
of THIQ (+)ꢀ1f in ethanol afforded single crystals which were analyzed by Xꢀray
diffraction. Colourless crystals, mp = 82–84 °C (ethanol).
f
R = 0.4 (petroleum
22
13a
ether/diethyl ether, 8:2). [
α]
D
= +57 (
c
1.0, CHCl
, 400 MHz)
= 13.6, 6.3 Hz, 1 H), 2.93 (ddd,
= 13.6, 7.8 Hz, 1 H), 3.21 (dm, = 13.8 Hz, 1 H), 3.33
= 13.8, 11.6, 4.7 Hz, 1 H), 3.73 (q, = 6.6 Hz, 1 H), 3.77 (t, = 6.8 Hz, 1 H),
= 7.6 Hz, 1 H), 6.75 (dm, = 8.7 Hz, 2 H), 6.85 (dm,
3
, 99:1 dr), lit. = +12 (0.6, CHCl
= 1.33 (d, = 6.5 Hz, 3 H), 2.51
= 16.8,
3
,
1
9
0 (S,S):10 (R,S) dr). H NMR (CDCl
3
δ
J
(ddd,
J
= 16.8, 6.8, 1.9 Hz, 1 H), 2.69 (dd,
J
J
1
1.5, 6.0 Hz, 1 H), 3.02 (dd,
J
J
(ddd,
J
J
J
3
.80 (s, 3 H), 6.60 (d,
J
J
J
= 8.7
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1
3
Hz, 2 H), 6.95–7.05 (m, 3 H), 7.08–7.15 (m, 5 H). C NMR (CDCl
3
, 100 MHz)
δ =
2
1
1.8 (p), 24.2 (s), 39.4 (s), 41.7 (s), 55.3 (p), 59.1 (t), 60.9 (t), 113.2 (t), 125.2 (t),
25.9 (t), 126.4 (t), 127.3 (t), 128.0 (t), 128.6 (t), 128.8 (t), 130.7 (t), 132.1 (q), 135.0
+
(q), 138.2 (q), 146.1 (q), 157.8 (q). HRMS (ESI , CH OH/CH Cl , 90:10, C H NO,
3
2
2
25 28
+
[
M + H] ) calcd for 358.2171, found 358.2170. Anal. Calcd for C25
H
27NO (357.49): C,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
3.99; H, 7.61; N, 3.92. Found: C, 84.27; H, 7.85; N, 3.96.
(1S,1’S)-(+)-1-(3,4-dimethoxybenzyl)-2(1-phenylethyl)-1,2,3,4-
13a
tetrahydroisoquinoline, (+)-1g. The synthesis of THIQ (+)ꢀ1g (1.65 g, 70%, 94:6
dr) was carried out according to procedure A, but with 1.97 g, (8.54 mmol, 1.4 equiv.)
of 4ꢀ(bromomethyl)ꢀ1,2ꢀdimethoxybenzene as the alkylating agent. The crude oily
residue was diluted with 5 mL of dichloromethane and poured into a chromatographic
column (50 × 2.5 cm), prepared with 30 g of silica and 8:2 petroleum ether/diethyl
ether. A slow crystallization of THIQ (+)ꢀ1g in ethanol afforded single crystals which
were analyzed by Xꢀray diffraction. Colourless crystals, mp = 88–90 °C (ethanol). Rf
22
1
=
0.3 (petroleum ether/diethyl ether, 8:2). [
NMR (CDCl , 400 MHz) = 1.34 (d, = 6.5 Hz, 3 H), 2.51 (dm,
= 13.6, 6.5 Hz, 1 H), 2.93 (ddd,
α
]
D
= +14.0 (
c
1.0, CHCl
= 17.0 Hz, 1 H),
= 17.0, 11.5, 5.8 Hz, 1 H), 3.02 (dd, J =
3
, 99:1 dr). H
3
δ
J
J
2.72 (dd,
J
J
13.6, 7.2 Hz, 1 H), 3.21 (dm,
J
= 13.8 Hz, 1 H), 3.31 (ddd, J = 13.8, 11.6, 4.7 Hz, 1
H), 3.67 (s, 3 H), 3.74 (q,
J
= 6.6 Hz, 1 H), 3.79 (t,
= 1.9 Hz, 1 H), 6.51 (dd, = 8.1, 1.9 Hz, 1 H), 6.60 (d,
= 8.1 Hz, 1 H), 6.95–7.05 (m, 3 H), 7.06–7.11 (m, 2 H), 7.12–7.16 (m, 3 H).
, 100 MHz) = 21.5 (p), 24.3 (s), 39.6 (s), 42.5 (s), 55.6 (p), 55.9 (p),
9.1 (t), 61.0 (t), 110.7 (t), 112.9 (t), 121.8 (t), 125.2 (t), 125.9 (t), 126.5 (t), 127.4 (t),
28.0 (t), 128.6 (t), 128.8 (t), 132.6 (q), 135.0 (q), 138.0 (q), 146.2 (q), 147.2 (q),
J
= 6.8 Hz, 1 H), 3.86 (s, 3 H), 6.33
(
d,
J
J
J
= 7.6 Hz, 1 H), 6.72 (d,
13
J
C
NMR (CDCl
3
δ
5
1
+
+
148.3 (q). HRMS (ESI , CH
3
OH/CH
88.2276, found 388.2275. Anal. Calcd for C26
.61. Found: C, 80.19; H, 7.52; N, 3.65.
2
Cl
2
, 9:1, C26 , [M + H] ) calcd for
H
30NO
2
3
3
H
29NO (387.52): C, 80.59; H, 7.54; N,
2
(1S,1’S)-(–)-2-(1-phenylethyl)-1(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1,2,3,4-
tetrahydroisoquinoline, (–)-1h, new compound. The synthesis of THIQ (–)ꢀ1h
(1.62 g, 70%, 95:5 dr) was carried out according to procedure A, but with 2.47 g,
(9.15 mmol, 1.5 equiv.) of 2ꢀ(3ꢀiodopropoxy)ꢀtetrahydroꢀ2
H
ꢀpyran as the alkylating
29
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