Total Synthesis of the Ortho-Hydroxylated Protoberberines (S)-Govaniadine, (S)-Caseamine, and (S)-Clarkeanidine via a Solvent-Directed Pictet-Spengler Reaction

Article abstract of DOI:10.1021/acs.joc.8b02378

The common para regioselectivity in Pictet-Spengler reactions with dopamine derivatives is redirected to the ortho position by a simple change of solvents. In combination with a chiral auxiliary on nitrogen, this ortho-selective Pictet-Spengler produced the 1-benzyltetrahydroisoquinoline alkaloids (S)-crassifoline and (S)-norcrassifoline and the bioactive 1,2-dioxygenated tetrahydroprotoberberine alkaloids (S)-govaniadine, (S)-caseamine, and (S)-clarkeanidine with high enantiopurity. Ortho/para ratios up to 89:19 and diastereomeric ratios up to 85:15 were obtained during formation of the B-ring. The general applicability of this solvent-directed regioselectivity was demonstrated with a second Pictet-Spengler reaction as required for C-ring formation of caseamine (o/p = 14:86 in trifluoroethanol) and clarkeanidine (o/p = 86:14 in toluene).

Full text of DOI:10.1021/acs.joc.8b02378

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Article
Total Synthesis of the Ortho-Hydroxylated Protoberberines
(S)-Govaniadine, (S)-Caseamine and (S)-Clarkeanidine
via a Solvent-directed Pictet-Spengler reaction
Brendan Horst, Martin J Wanner, Steen Ingemann Jorgensen, Henk Hiemstra, and Jan H. van Maarseveen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02378 • Publication Date (Web): 19 Nov 2018
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Total Synthesis of the Ortho-Hydroxylated Protoberberines (S)-Govaniadine,
(S)-Caseamine and (S)-Clarkeanidine via a Solvent-directed Pictet-Spengler
reaction
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Brendan Horst, Martin J. Wanner, Steen Ingemann Jørgensen, Henk Hiemstra and Jan H. van
Maarseveen*
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Van ‘t Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The
Netherlands
ABSTRACT
HO
CHO
NH
Ar
MeO
HN
Ph
MeO
PhMe, D
OH
OR2
OR1
B
H2CO,
TFE, rt
N
C
MeO
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H2CO,
HCl, D
H
HO
H2CO,
PhMe, D
OMe
(S)-caseamine
OH
N
MeO
H
HO
N
MeO
H
HO
OH
OMe
O
O
(S)-govaniadine
(S)-clarkeanidine
The common para-regioselectivity in Pictet-Spengler reactions with dopamine derivatives is redirected to the
ortho-position by a simple change of solvents. In combination with a chiral auxiliary on nitrogen this ortho-
selective Pictet-Spengler produced the 1-benzyltetrahydro-isoquinoline alkaloids (S)-crassifoline, (S)-
norcrassifoline and the bioactive 1,2-dioxygenated tetrahydro-protoberberine alkaloids (S)-govaniadine, (S)-
caseamine and (S)-clarkeanidine with high enantiopurity. Ortho/para ratios up to 89:19 and diastereomeric ratios
up to 85:15 were obtained during formation of the B-ring. The general applicability of this solvent-directed
regioselectivity was demonstrated with a second Pictet-Spengler reaction as required for C-ring formation of
caseamine (o/p = 14:86 in trifluoroethanol) and clarkeanidine (o/p = 86:14 in toluene).
INTRODUCTION
Most of the 1-benzyltetrahydroisoquinoline alkaloids found in nature are formed from dopamine and contain a
6,7-dioxygenated substitution pattern in the A-ring as a result of enzyme-catalyzed Pictet-Spengler condensations
(Fig 1).1,2 Isomeric 1-benzyltetrahydroisoquinolines with oxygen substituents at C-7 and C-8 are less abundant in
nature, but display interesting biological properties.3 Examples of more complex alkaloids derived from 7,8-
dioxygenated 1-benzyltetrahydroisoquinolines are the parent compound crassifoline (3), several
tetrahydroprotoberberines (e.g. govaniadine (4)), the cularine alkaloids (5)4 and pavine alkaloids such as
neocaryachine (6). Labelling studies performed by Müller and Zenk5 to elucidate the biosynthesis of crassifoline
and the cularine alkaloids showed that this unusual oxygenation pattern in the tetrahydroisoquinoline ring is not
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formed by oxygen transposition, but most likely by an ortho selective Pictet-Spenglerase, although this enzyme
has not yet been described in literature.
The enantioselective chemical syntheses of 6,7-oxygenated 1-benzyltetrahydroisoquinolines preferably follow the
lines of the biosynthesis. In particular the Bischler-Napieralski method, in combination with asymmetric
hydrogenation, or by chiral auxiliary directed hydride reduction is favored for enantioselective preparations
(reviewed by Rozwadowska in 2004 and 2016, see ref. 2). A practical synthesis of the 7,8-dioxygenated
tetrahydroisoquinoline ring system, however, is not accessible via the Bischler-Napieralski reaction, which
exclusively yields para products. Likewise, the Pictet-Spengler approach with chiral (organo)catalysis, or with
assistance of chiral auxiliaries, is only effective for the traditional 6,7-substitution pattern.2,3,6,7 A few methods are
described to prepare this 7,8-substitution pattern and these are not based on Pictet-Spengler or Bischler-Napieralski
approaches, but require multistep quinoline ring construction. Rodrigues described an efficient build-up/chiral
auxiliary approach to ortho-hydroxylated crassifoline and the cularine alkaloids.4a Halogen atoms as temporary
blocking substituents at positions in the aromatic ring that should stay unsubstituted are also applied.4b
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Figure 1. The general biocatalytic Pictet-Spengler reactions and some examples of alkaloids based on the
7,8-dioxygenated tetrahydroisoquinoline-structure
Ortho selectivity towards an activating substituent in Mannich type cyclizations is more often observed, but in the
Pictet-Spengler reaction, ring closure ortho to the phenolic substituent is always a minor process in comparison to
the para position. The pH dependency of ortho/para ratios was investigated by Bates, who found pH 7 as an
optimum for ortho product formation (o/p = 50:50) using formaldehyde or acetaldehyde.8
In a previous publication on the synthesis of javaberine alkaloids we reported that the regioselectivity of the Pictet-
Spengler reaction between secondary phenylethylamines and aldehydes depends strongly on the solvent and varies
between 99% para selectivity in trifluoroethanol to 81% ortho selectivity in aprotic, apolar solvents without
addition of external acids (Scheme 1).7a
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Scheme 1. Ortho selective Pictet-Spengler reaction towards the javaberine synthesis (ref 7a)
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Furthermore, both ortho and para products were formed as single diastereomers. To translate this uncatalyzed
Pictet-Spengler procedure9 to both the challenging ortho-regioselectivity and enantioselectivity in the 1-
benzyltetrahydroisoquinoline series we herein disclose a chiral auxiliary approach, starting from a (S)-(–)-α-
methylbenzyl functionalized dopamine analogue.10
RESULTS AND DISCUSSION
The benzene ring in the dopamine part of the key precursor 10 (Scheme 2) requires activation by a free phenolic
OH, to allow non-acid-catalyzed Pictet-Spengler reactions with dopamine derivatives. If methoxy or
methylenedioxy substituents are the activating substituents, strongly acidic catalysts are required that produce
almost exclusively para substituted Mannich-type products.2 The required phenylethylamine 10 was prepared from
phenylacetaldehyde 9 that was obtained after a convenient Wittig/hydrolysis homologation process7,15 starting
from isovanilline (7). Reductive amination of phenylacetaldehyde 9 with (S)--methylbenzylamine gave chiral
dopamine analogue 10. To optimize the Pictet-Spengler conditions we selected (S)-govaniadine 4, a 1,2-
oxygenated tetrahydroprotoberberine alkaloid that has not been synthesized before (Scheme 2). Govaniadine is
isolated from Corydalis govaniana Wall. and has been the subject of different studies on its biological activity
since its discovery in 2013.11 These studies revealed significant analgesic activity for govaniadine, similar to that
of ibuprofen, due to its potential binding to the COX-2 enzyme.12 Furthermore, high and selective leishmanicidal
activity13, anti-urease activity10 and glucoronidase inhibition were reported.14
The Pictet-Spengler reaction of aldehyde 1116 with equimolar amounts of 10 in different solvents was monitored
by NMR, and shows a clear solvent-dependent ortho/para distribution of the product (Table 1). Protic solvents,
with TFE as the strongest proton donor, gave fast reactions with high preference for the para isomer 17, which is
typical for a process that is acid catalyzed. Reactions in toluene and dichloroethane, both performed at higher
dilution to prevent intermolecular catalysis by the phenolic OH, were considerably slower, but gave good
selectivity for the ortho isomer 15.
Scheme 2. Ortho and para product formation: activation of the enamine intermediate in aprotic and
protic solvents
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Table 1. Ortho/para ratios in the Pictet-Spengler cyclization of 10
Entry Solvent
T (°C) time ortho/para a dr ortho b
(15/17)
(15/16)
1
2
3
4
5
TFE
75
1 h
2 d
2 d
4 d
4 d
10:90
38:62
65:35
72:28
81:19
53:47
60:40
60:40
85:15
73:27
methanol 65
MeCN
DCE c
toluene c 105
80
80
aAt >80% conversion, determined by 1H NMR. bThe para isomer was formed as a ca. 50:50 mixture of
inseparable diastereomers. c Performed at 40 mM. TFE = 2,2,2-trifluoroethanol, DCE = 1,2-dichloroethane.
Importantly, the diastereomeric ratio of the ortho isomers 15, with the required (S)-configuration at C-117 and 16
(R-configuration at C-1, not shown) in toluene and dichloroethane was good, and the isomers were readily
separable by chromatography. This is in sharp contrast with the para isomer 17, which was formed exclusively as
an inseparable mixture of both diastereomers in nearly equal amounts. NMR-spectra of the crude reaction mixtures
at an early stage showed that the reactants were converted into the unstable, E-enamine 12. An explanation for the
high (S)-preference at C-1 in the ortho isomer can be found in reaction intermediate 13, assuming that the
intramolecular hydrogen bonded structure shown in Scheme 2 is favoured in aprotic solvents. The compact
structure of intermediate 13 enhances approach of the aromatic ring from the top side of the iminium ion. In toluene
the highest ortho/para ratio was obtained, while DCE gave a better diastereomeric ratio. Since the yields in both
solvents were comparable, toluene was selected for scaling up the synthesis, providing pure 15 in 48% isolated
yield. Debenzylation of 15 to 18 and cyclization of the C-ring with formaldehyde under acidic conditions produced
(S)-(−)-govaniadine 4, which was identical to the natural product (Scheme 3).11 Final analysis of the recrystallized
product (>99% ee) gave an optical rotation which is typical for such systems: [α]D20 −339 (c = 0.55, methanol).
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This optical rotation is significantly larger than the one reported in literature ([α]D20 −59.9 (c = 0.1, methanol),
indicating that the product isolated from Corydalis govaniana Wall. was not optically pure.11
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Scheme 3. Synthesis of govaniadine
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The next targets nor-crassifoline (23) and crassifoline (3) were readily prepared via the same sequence, starting
from phenethylamine 10 and TBS-protected homo-isovaniline 197b (Scheme 4). Comparable yields and
selectivities were obtained from the Pictet-Spengler reaction in toluene, producing 45% of the desired isomer 20
after chromatographic purification. Hydrogenolysis of the chiral auxiliary gave nor-crassifoline 23, which was
reductively methylated to crassifoline 3.
Scheme 4. Synthesis of caseamine and clarkeanide via nor-crassifoline
Nor-crassifoline (23) was also used as the synthetic precursor for the related protoberberines caseamine (2418),
displaying activity against urease11, and clarkeanidine (2519). Biosynthetically, the ring closure of 1-
benzyltetrahydroisoquinolines to tetrahydroprotoberberines does not proceed with formaldehyde, but via the
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berberine bridging enzyme (BBE) catalyzed oxidation of N-methylated benzyltetrahydroisoquinolines,
immediately followed by ring closure of the intermediate methylene iminium salt (Scheme 5).20
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Scheme 5. Ortho vs para selectivity in tetrahydroberberine synthesis
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H
OH
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R1 = Me
BBE
NR1
RO
26 (‘ortho’)
R1 = H
H
H2C=O/H+
27
RO
RO
N
RO,HO
H
28 (‘para’) RO,HO
A clear preference of this enzyme for ring-closure ortho to the phenolic OH (26) is observed, which hampers the
synthesis of para products via biocatalytic routes.21 Similar to the synthetic Pictet-Spengler approaches under
traditional protic conditions using formaldehyde and a free NH substrate, the para isomer is formed exclusively
when alkoxy groups are used as the activating substituents,2 as we also have shown in the govaniadine synthesis
(Scheme 2). When a free phenolic OH is the activator, the para-product (28) is always formed in excess, but is
accompanied by some ortho product.22,23,24 Application of the solvent directed Pictet-Spengler process (see Scheme
2) to the tetrahydroprotoberberine synthesis with nor-crassifoline and formaldehyde selectively produced both
isomers under mild conditions (Scheme 4). The para-isomer (S)-caseamine 24 was obtained by reaction of 23 with
formaline in trifluoroethanol (64%, o:p = 14:86, >99% ee after recrystallization, [α]D20 −314, lit18 −328). Starting
from 23 under aprotic conditons using paraformaldehyde in toluene the ortho isomer (S)-clarkeanide 25 was
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formed (55%, o:p = 86:14, 95% ee after crystallization, [α]D −442, lit19 −277).
In conclusion, we have shown that Pictet-Spengler reactions under apolar conditions can produce the otherwise
difficult to access ortho-oxygenated products. The chiral auxiliary-supported route is straightforward, scalable and
in particular suitable for high diastereoselectivety in ortho hydroxylated tetrahydroisoquinoline preparations. In
addition, application of this solvent directed Pictet-Spengler approach to regioselective tetrahydroprotoberberine
synthesis provides a useful addition to existing methods.
EXPERIMENTAL SECTION
1. General information. Anhydrous CH2Cl2 and CH3CN were freshly distilled from CaH2. Dried THF was
obtained by distillation from sodium/benzophenone. DMF and DMSO on 4Å molecular sieves were obtained from
Sigma-Aldrich and stored under N2 atmosphere. Toluene was distilled and stored on 4Å molecular sieves.
Reagents were purchased with the highest purity (usually >98%) from Sigma Aldrich and Fluorochem and used
as received. Reactions were monitored by thin layer chromatography (TLC) carried out on 0.25 mm E. Merck
silica gel plates (60F-254). SilaFlash® P60 (particle size 40-63 µm) was used for silica column chromatography.
NMR spectra were recorded on Bruker DRX-500, 400 and 300 MHz instruments and calibrated on residual
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undeuterated solvent signals as internal standard. The H-NMR multiplicities were abbreviated as followed: s =
singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet. High resolution mass spectra (HRMS)
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were recorded on a AccuTOF GC v 4g, JMS-T100GCV Mass spectrometer (JEOL, Japan). FD/FI probe equipped
with a FD emitter of 10 μm. Current rate 51.2 mA/min over 1.2 min machine using field desorption (FD) as
ionization method. IR spectra were recorded on a Bruker Alpha FTIR machine. Chiral HPLC was performed with
a Shimadzu LC-20AD with Shimadzu SPD-M20A diode array detector, using a Daicel Chiralcel AD column
(eluent n-heptane/isopropanol 70/30, flow 1.000 mL/min, λ 230 nm).
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2. Synthetic procedures
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2-Methoxy-5-(2-methoxyethenyl)phenol 8.15 KOt-Bu (22.4 g, 200 mmol) was added in 3 portions, with intervals
of 3 minutes, to an efficiently stirred suspension of methoxymethyltriphenyl phosphonium
chloride (34.3 g, 100 mmol) in dry THF (250 mL) with ice cooling. After additional
stirring for 5 min, isovanilline 7 (13.7 gr, 90 mmol) was added in 3 portions, with intervals
of 2 minutes, to the reaction mixture resulting in a rapid colour change from red to yellow. The cooling bath was
removed and the mixture was stirred at rt for 5 h. Silica gel was added (150 g), the solvents were evaporated
thoroughly and the residue was put on top of a silica column. Flash chromatography (petroleum ether/ethyl acetate
4/1, 3/1 and 2.5/1) gave 8 (13.3 g, 73.9 mmol, 82%, 45:55 E/Z mixture) as an oil, which solidified upon standing.
The spectra were identical with the ref 15:1H NMR (400 MHz, CDCl3) δ 7.09 (dd, J = 8.4, 2.1 Hz, 1H), 7.05- 6.93
(m, 2H), 6.87-6.69 (m, 3H), 6.12 (s, 1H), 6.08 (d, J = 7.0 Hz, 1H), 5.82 (d, J = 12.9 Hz, 1H), 5.20 (d, J = 7.0 Hz,
1H), 3.825 (s, 3H), 3.82 (s, 3H), 3.74 (s, 3H), 3.68 (s, 3H).
2-(3-Hydroxy-4-methoxyphenyl)acetaldehyde 9. A mixture of TFA (5 mL) and water (5 mL) was added to a
solution of enol ether 8 (7.39 g, 41.0 mmol) in DCM (200 mL). The resulting
heterogenous mixture was stirred vigorously overnight at rt. Water was added and after
separation the organic layer was washed with NaHCO3 aq. and dried over Na2SO4.
Chromatographic separation (2/1 and 3/2 petroleum ether /ethyl acetate) gave pure 9 (3.75 g, 24.7 mmol, 60%) as
1
an oil, which solidified in the freezer: H NMR (400 MHz, CDCl3) δ 9.66 (t, J = 2.4 Hz, 1H), 6.83 (dd, J = 8.2,
1.0 Hz, 1H), 6.78 (d, J = 2.1 Hz, 1H), 6.67 (dd, J = 8.2, 2.1 Hz, 1H), 6.12 (s, 1H), 3.83 (s, 3H), 3.55 (d, J = 2.4 Hz,
2H); 13C{1H} NMR (101 MHz, CDCl3) δ 199.7, 145.9, 145.8, 124.6, 120.9, 115.7, 111.0, 55.7, 49.5.
(S)-2-Methoxy-5-(2-((1-phenylethyl)amino)ethyl)phenol 10. Aldehyde 9 (3.74 g, 22.5 mmol) and (S)-(–)-α-
methylbenzylamine (3.1 mL, 24 mmol) were dissolved in THF (75 mL) and stirred at 0
°C for 30 min. Sodium triacetoxyborohydride (10.6 g, 50 mmol) was added and the
mixture was stirred at 0 °C for 30 min and at rt for 14 h. The solvent was evaporated and
the residue was dissolved in ethyl acetate and washed with Na2CO3 solution and water.
Next the product was extracted from the organic layer with aqueous HCl (3x 100 mL). The water layer was
washed three times with ethyl acetate, before the water layer was basified with Na2CO3 solution. Extraction with
ethyl acetate, drying over Na2SO4 and evaporation of the solvent gave chiral amine 10 (5.02 g, 18.5 mmol, 82%)
as a solid: Mp 86–92 °C; 1H NMR (400 MHz, CDCl3) δ 7.45-7.14 (m, 5H), 6.81-6.73 (m, 2H), 6.66 (dd, J = 8.2,
2.3 Hz, 1H), 5.65 (bs, 1H), 3.88 (s, 3H), 3.78 (q, J = 6.7 Hz, 1H), 2.87-2.47 (m, 4H), 1.35 (d, J = 6.7 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 146.0, 145.6, 145.0, 132.8, 128.5, 127.0, 126.7, 119.7, 115.5, 111.1, 58.2, 55.9,
48.7, 35.3, 23.9; HRMS (ESI+): m/z calculated for C17H22NO2 (M+H)+ 272.1651, found 272.1642.
(S)-5-(2-((Benzo[1,3]dioxol-5-yl)vinyl)(1-phenylethyl)amino)ethyl-2-methoxyphenol 12. An equimolar
solution of 10 and 11 in toluene was refluxed for 20 min. Evaporation of the solvent
gave unstable enamine 12, mixed with small amounts of starting materials and Pictet-
Spengler products: 1H NMR (400 MHz, CDCl3) δ ; 7.42–7.13 (m, 10H), 6.87 (d, J =
14.0 Hz, 1H), 6.82– 6.68 (m, 5H), 6.64 (dd, J = 8.1, 1.8 Hz, 2H), 5.92 (s, 2H), 5.31 (d,
J = 14.0 Hz, 1H), 4.45 (q, J = 7.0 Hz, 1H), 3.89 (s, 3H), 3.20 (m, 2H), 2.72 (m, 2H), 1.56 (d, J = 7.0 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 148.0, 145.7, 145.2, 143.8, 142.8, 137.8, 135.0, 134.8, 133.1, 129.1, 128.7,
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128.5, 128.4, 128.4, 128.2, 127.5, 127.2, 127.0, 126.9, 126.9, 125.3, 120.1, 120.0, 116.9, 115.1, 115.0, 110.8,
108.5, 103.5, 100.7, 100.5, 97.1, 61.4, 55.9, 55.9, 55.9, 49.6, 33.2, 21.5, 19.1.
Pictet-Spengler of 10 with aldehyde 11. A solution of 10 (0.542 g, 2.0 mmol) and homopiperonal 1116 (0.345 g,
2.1 mmol) in anhydrous toluene (50 mL) was stirred at 105 °C for 4 days. Evaporation of
the solvent and separation by flash chromatography (petroleum ether /ethyl acetate 19/1,
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10/1 and 4/1) provided first the minor (R)-ortho isomer 16 (0.150 g, 0.360 mmol, 18%),
next the desired isomer 15 (0.401 g, 0.962 mmol, 48 %) and finally an inseparable mixture
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of two para isomers 17 (0.135 g, 0.324 mmol, 16%).
16: [α]D20 −2.0 (MeOH, c = 2.1); 1H NMR (500 MHz, CDCl3) δ 7.31-7.24 (m, 2H), 7.25-
7.19 (m, 3H), 6.97 (s, 1H), 6.87 (d, J = 7.9 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 6.64 (d, J
= 8.2 Hz, 1H), 6.11-5.92 (m, 2H), 5.80 (s, 1H), 4.50 (dd, J = 10.3, 3.0 Hz, 1H), 3.92 (s, 3H), 3.70 (q, J = 6.4 Hz,
1H), 3.31-3.15 (m, 1H), 3.06 (dd, J = 13.7, 3.0 Hz, 1H), 2.89-2.78 (m, 2H), 2.77-2.70 (m, 1H), 2.27-2.20 (m, 1H),
1.03 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 146.9, 146.4, 145.3, 143.9, 142.3, 135.7, 128.4, 128.1,
127.2, 126.5, 125.0, 122.5, 119.4, 110.3, 108.8, 107.4, 100.5, 57.7, 56.0, 54.2, 39.6, 39.5, 22.5, 21.8; IR (neat): ν
3514, 1487 cm-1; HRMS (FD+): m/z calculated for C26H28NO4 (M+H)+ 418.2018, found 418.2006.
15: [α]D20 +41.9 (MeOH, c = 1.0); 1H NMR (500 MHz, CDCl3) δ 7.13-7.06 (m, 1H), 7.05 (t, J = 7.4 Hz, 2H), 6.84
(d, J = 7.4 Hz, 2H), 6.76 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 7.7 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 6.64-6.56 (m, 2H),
5.97 (s, 2H), 5.63 (s, 1H), 3.96 (dd, J = 10.3, 2.9 Hz, 1H), 3.89 (s, 3H), 3.63 (q, J = 6.4 Hz, 1H), 3.47-3.38 (m,
1H), 3.33 (dd, J = 14.6, 5.8 Hz, 1H), 3.01-2.84 (m, 2H), 2.74 (dd, J = 13.7, 10.3 Hz, 1H), 2.53-2.34 (m, 1H), 1.29
(d, J = 6.4 Hz, 3H); C{1H} NMR (101 MHz, CDCl3) δ 146.9, 146.1, 145.4, 144.0, 142.7, 135.1, 128.4, 127.8,
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127.5, 126.2, 125.1, 122.7, 119.3, 110.4, 108.7, 107.5, 100.5, 58.9, 56.6, 56.0, 39.6, 38.7, 22.3, 22.1; IR (neat): ν
3533, 1489 cm-1; HRMS (FD+): m/z calculated for C26H28NO4 (M+H)+ 418.2018, found 418.2015.
17 (mixture of diastereomers: 1H NMR (500 MHz, CDCl3, selected signals) 7.34 (d, J = 4.6 Hz, 4H), 7.24-7.19
(m, 2H), 7.13 (t, J = 5.4 Hz, 2H), 6.74 (d, J = 7.8 Hz, 1H), 6.69 (dd, J = 10.7, 8.5 Hz, 2H), 6.60-6.58 (m, 1H), 6.52
(dd, J = 7.9, 1.7 Hz, 1H), 6.48-6.39 (m, 1H), 6.07 (s, 1H), 5.95 (d, J = 2.2 Hz, 2H), 4.02 (d, J = 8.1 Hz, 1H), 3.96-
3.75 (m, 2H), 3.70 (s,1H), 3.69 (s, 3H), 3.63 (s, 1H), 3.34-3.21 (m, 1H), 3.19 (s, 1H), 3.17-3.01 (m, 1H), 2.85 (m,
3H), 2.80-2.61 (m, 2H), 2.52-2.27 (m, 2H), 1.39 (d, J = 6.6 Hz, 3H).
(S)-1-(Benzo[1,3]dioxol-5-ylmethyl)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-8-ol 18. Pictet-Spengler
product 15 (0.590 g, 1.41 mmol) was dissolved in ethanol (20 mL) and palladium
hydroxide on carbon (10% w/w, 0.190 g) was added. The reaction flask was flushed with
hydrogen and stirred for 18 h at 60 °C under hydrogen atmosphere. The mixture was
filtered over celite, the residue was washed with ethanol (100 mL) and the combined
filtrates were evaporated. Chromatographic purification (silica gel, petroleum ether/ethyl
acetate/Et3N 50:50:3 gave 18 as a light yellow glass (0.438 g, 1.40 mmol, 99%): [α]D
20
+12 (MeOH, c = 0.28); 1H NMR (400 MHz, CDCl3) δ 6.85 (d, J = 1.7 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.78-
6.70 (m, 2H), 6.63 (d, J = 8.3 Hz, 1H), 5.96 (s, 2H), 4.33 (dd, J = 10.6, 2.7 Hz, 1H), 3.85 (s, 3H), 3.23 (m, 2H),
2.99 (ddd, J = 12.1, 6.0, 2.6 Hz, 1H), 2.93-2.73 (m, 2H), 2.67 (dt, J = 16.1, 3.5 Hz, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 147.6, 145.8, 144.2, 142.0, 134.2, 128.1, 125.5, 122.1, 119.5, 109.6, 108.9, 108.1, 100.7, 56.0, 53.2,
37.9, 37.5, 28.8; HRMS (FD+): m/z calculated for C18H20NO4 (M+H)+ 314.1392, found 314.1400.
(S)-Govaniadine 4.11,12 Amine 18 (44.8 mg, 0.142 mmol) was dissolved in ethanol, conc. HCl (50 l) was added,
the volatiles were evaporated and the residue was coevaporated with ethanol. The
hydrochloride was redissolved in ethanol (1 mL), water (1.5 mL) and aqueous
formaldehyde (37%, 1.5 mL) and this solution was refluxed for 6 h. The volatiles were
evaporated and the residue was stirred with aqueous Na2CO3 and ethyl acetate until
dissolved. Extractive workup and chromatographic purification (silica gel, petroleum
ether/ethyl acetate 50/50 and 0/100) gave (S)-govaniadine (28.1 mg, 0.0875 mmol, 61%)
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as a crystallizing glass. Recrystallization from methanol gave enantiopure (S)-govaniadine (4): ee > 99% (Chiralcel
AD column, eluent n-heptane/isopropanol 70:30, flow 1.000 mL/min); [α]D20 −339 (MeOH, c = 0.55), lit:11 [α]D
20
−59.9 (c = 0.1, MeOH); Mp 141-144 °C; 1H NMR (400 MHz, CDCl3 + 10% CD3OD) δ 6.75 (d, J = 8.3 Hz, 1H),
6.65 (d, J = 8.3 Hz, 1H), 6.58 (s, 1H), 6.55 (s, 1H), 5.89 (s, 2H), 4.06-3.93 (m, 2H), 3.88 (s, 3H), 3.71-3.59 (m,
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1H), 3.16-2.92 (m, 2H), 2.85-2.55 (m, 3H). C{1H} NMR (101 MHz, CDCl3 + 10% CD3OD) δ 145.9, 145.6,
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144.3, 142.4, 128.2, 128.1, 126.7, 124.4, 119.4, 108.9, 108.6, 106.0, 100.4, 57.7, 56.1, 55.9, 48.4, 32.2, 29.3; IR
(neat): ν 3507, 1488 cm-1. HRMS (FD+): m/z calculated for C19H19NO4 (M)+ 325.1314, found 325.1325.
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19
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Pictet-Spengler with aldehyde 19. A mixture of amine 10 (1.084 g, 4.0 mmol) and aldehyde 197a,b (1.12 g, 4.0
mmol) was heated at 105 °C in anhydrous toluene (100 mL, 40 mM) during 5 days.
Separation by flash chromatography (petroleum ether/ethyl acetate, 12/1, 10/1)
provided first the minor 1-(R)-ortho isomer 21 (0.462 g, 0.867 mmol, 21.7%), next the
desired 1-(S)-ortho isomer 20 (0.962 g, 1.80 mmol, 45%) and finally an inseparable
mixture of two para isomers in a ca. 1/1 ratio (0.221 g, 0.42 mmol, 16%).
21: [α]D20 −2.3; H NMR (400 MHz, CDCl3) δ 7.30-7.20 (m, 5H), 6.99-6.90 (m, 2H),
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6.85 (d, J = 8.1 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 5.78 (s,
1H), 4.52 (dd, J = 9.9, 2.9 Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.69 (q, J = 6.3 Hz, 1H), 3.29-3.12 (m, 1H), 3.04
(dd, J = 13.6, 3.0 Hz, 1H), 2.90-2.76 (m, 2H), 2.70 (dd, J = 14.0, 6.0 Hz, 1H), 2.21 (dd, J = 16.6, 4.7 Hz, 1H), 1.06
13
(s, 9H), 1.03 (d, J = 6.3 Hz, 3H), 0.21 (s, 3H), 0.20 (s, 3H); C{1H} NMR (101 MHz, CDCl3) δ 149.0, 146.6,
144.3, 144.0, 142.4, 134.6, 128.6, 128.1, 127.3, 126.5, 125.3, 122.8, 122.6, 119.4, 111.5, 108.7, 57.8, 56.1, 55.7,
54.2, 39.5, 39.3, 25.8, 22.6, 21.9, 18.5; HRMS (FD+): m/z calculated for C32H44NO4Si (M+H)+ 534.3034, found
534.3016. 20: [α]D20 +10.5; 1H NMR (400 MHz, CDCl3) δ 7.2-7.1 (m, 3H), 6.8 (m, 2H), 6.85-6.76 (m, 3H), 6.76-
6.63 (m, 2H), 5.68 (s, 1H), 4.09 (dd, J = 9.9, 3.0 Hz, 1H), 3.91 (s, 3H), 3.915 (s, 3H, 3.73 (q, J = 6.5 Hz, 1H), 3.56
-3.42 (m, 1H), 3.33 (dd, J = 14.4, 5.5 Hz, 1H), 3.05-2.89 (m, 2H), 2.89-2.72 (m, 1H), 2.49 (dd, J = 16.4, 4.3 Hz,
1H), 1.33 (dd, J = 6.5 Hz, 3H), 1.12 (s, 9H), 0.27 (s, 3H), 0.26 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 149.0,
146.1, 144.1, 143.9, 142.6, 133.9, 128.5, 127.8, 127.3, 126.1, 125.3, 123.0, 122.8, 119.2, 111.9, 108.5, 58.9, 56.4,
55.9, 55.9, 38.9, 38.7, 29.4, 25.8, 22.7, 22.0, 18.4; HRMS (FD+): m/z calculated for C32H44NO4Si (M+H)+
534.3040, found 534.3077. Para isomers 1H NMR (400 MHz, CDCl3, selected signals) δ 6.01 (s, 1H), 5,85 (s),
4.02 (t, J = 6.8 Hz, 1H), 3.80 (s, 1H), 3.64 (s, 2H), 3.57 (s, 1H), 1.40 (d, J = 6.5 Hz, 2H), 1.28 (d, J = 6.5 Hz, 2H),
13
0.98 (s, 1H); C{1H} NMR (101 MHz, CDCl3) δ 149.2, 149.1, 145.5, 144.5, 144.5, 143.9, 143.8, 143.7, 133.1,
132.8, 129.1, 128.4, 128.2, 128.2, 128.1, 127.6, 127.4, 127.3, 127.2, 127.1, 126.8, 126.5, 123.1, 123.0, 122.5,
122.3, 120.3, 119.9, 114.2, 114.2, 111.9, 111.8, 111.6, 110.8, 110.4, 60.7, 59.5, 59.1, 58.8, 55.8, 55.7, 55.6, 55.5,
55.5, 55.4, 55.3, 41.7, 40.6, 40.2, 39.7, 25.8, 25.7, 25.6, 25.6, 24.4, 23.6, 22.3, 22.0, 18.4, 18.3.
(S)-1-(3-Hydroxy-4-methoxybenzyl)-7-methoxy-2-((S)-1-phenylethyl)-1,2,3,4-tetrahydroisoquinolin-8-ol
hydrochloride 22. A solution of 20 (0.587 g, 1.1 mmol) in methanol (20 mL) was
stirred with HCl conc. (2 mL) during 18 h at rt. The solvents were evaporated and
the residue was evaporated three times with methanol to remove water and TBSOH
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to give 22 (hydrochloride, 0.453g, 1.08 mmol, 98%) as a dark glass: H NMR (400
MHz, CD3OD) δ 7.53-7.45 (m, 1H), 7.43-7.36 (m, 2H), 7.11-7.05 (m, 2H), 7.03 (d,
J = 8.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.45-6.37 (m, 2H),
4.81-4.75 (m, 1H), 4.35 (q, J = 6.8 Hz, 1H), 4.01-3.91 (m, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.87-3.77 (m, 2H), 3.30-
3.04 (m, 2H), 2.94 (dd, J = 15.6, 10.2 Hz, 1H), 1.72 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (101 MHz, CD3OD) δ 148.7,
147.9, 147.5, 144.6, 137.2, 131.0, 130.7, 129.0, 128.9, 124.1, 121.6, 120.7, 118.2, 117.3, 113.1, 112.9, 64.0, 60.0,
56.8, 56.6, 43.0, 38.8, 22.3, 18.6; HRMS (FD+): m/z calculated for C26H30NO4 (M+H)+ 420.2169, found 420.2160.
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Debenzylation to norcrassifoline 23. 22 (0.400 g, 0.877 mmol) was stirred with 10% Pd/C (0.15 g) in 12 mL
ethanol under H2 at atmospheric pressure during 18 h. Filtration over celite and
evaporation gave norcrassifoline 23 (hydrochloride, 0.276 g, 0.88 mmol, 100%) as a
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brownish glass: [] = no transmission; H NMR (400 MHz, CD3OD) δ 7.07-6.92
(m, 2H), 6.92-6.79 (m, 2H), 6.74 (d, J = 8.3 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.54
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(m, 2H), 3.3-3.2 (m, 2H), 3.03 (m, 2H), 2.91 (dd, J = 15.1, 10.5 Hz, 1H); C{1H}
NMR (101 MHz, CD3OD) δ 148.7, 148.1, 147.4, 144.3, 129.9, 125.1, 121.8, 120.7,
120.2, 117.2, 113.3, 112.7, 58.4, 56.8, 56.6, 55.0, 50.0, 49.8, 49.6, 49.4, 49.1, 48.9,
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48.7, 48.5, 39.0, 37.6, 25.7, 18.5; HRMS (FD+): m/z calculated for C18H22NO4 (M+H)+ 316.1549, found 316.1555.
(S)-(+)-Crassifoline 3.4 A mixture of 22 (hydrochloride, 35.1 mg, 0.10 mmol), paraformaldehyde (35 mg, 0.80
mmol), sodium acetate (33 mg, 0.40 mmol), sodium cyanoborohydride (33.0 mg, 0.54
mmol) and zinc chloride (35.0 mg, 0.26 mmol) was stirred in methanol (4 mL) for 24
h at rt.7b Silica gel was added and the residue obtained after evaporation was applied
to a silica column. Eluting with ethyl acetate, ethyl acetate/MeOH/Et2NH 95/3/2 and
ethyl acetate/MeOH/Et2NH 90/7/3 gave crassifoline 3 (23.7 mg, 0.072 mmol, 72%) as
a glass: [α]D20 +17.6 (c = 0.5 in MeOH), Lit4,5 [α]D20 +20 (c = 0.5 in MeOH); 1H NMR
(400 MHz, CDCl3) δ 6.96 (d, J = 1.8 Hz, 1H), 6.78 (d, J = 1.7 Hz, 1H), 6.75 (d, J =
8.5 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 5.79 (bs, 2H), 4.10 (dd, J = 9.4, 3.0 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.30
(ddd, J = 12.9, 10.5, 5.0 Hz, 1H), 3.01 (dd, J = 14.3, 3.0 Hz, 1H), 2.95-2.70 (m, 3H), 2.51-2.41 (m, 1H), 2.37 (s,
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3H); C{1H} NMR (101 MHz, CDCl3) δ 145.2, 144.9, 144.2, 142.5, 134.3, 127.2, 124.3, 120.5, 119.2, 115.6,
110.4, 109.0, 60.2, 56.1, 55.9, 44.9, 42.4, 38.8, 22.9; HRMS (FD+): m/z calculated for C19H24NO4 (M+H)+
330.1700, found 330.1689.
(S)-(-)-Caseamine 24.18 A solution of norcrassifoline 23 (free base, 45 mg, 0.125 mmol) and 37% aqueous
formaldehyde (30 l, 0.4 mmol) in trifluoroethanol (1.0 mL) was stirred during 5 h
at rt. Caseamine 24 (21.8 mg, 0.066 mmol, 53%) directly crystallizes from the
reaction mixture. Chromatography (ethyl acetate and ethyl acetate/MeOH 97/3 gave
additional caseamine (4.5 mg, total yield 0.080 mmol, 64%) and clarkeanidine 25
(4.4 mg, 0.013 mmol, 10%, spectra see next experiment). Caseamine 2418 ee 99%
(Chiralcel AD column, eluent n-heptane/isopropanol 70:30, flow 1.000 mL/min);
[α]D20 −314 (CHCl3 + MeOH, c = 0.15), lit18 [α]D −328 (c = 0.04, CHCl3); Mp 246-
250 °C (lit18 246-247 °C); 1H NMR (300 MHz, d6-DMSO, partial overlap by solvent peaks) δ 8.64 (s, 1H), 8.54
(s, 1H), 6.79 (d, J = 8.2 Hz, 1H), 6.62 (s, 1H), 6.55 (d, J = 8.2 Hz, 1H), 6.46 (s, 1H), 3.80 (s, 2H), 3.77 (s, 3H),
3.73 (s, 3H), 3.46-3.36 (m, 1H), 2.96 (dt, J = 10.4, 4.8 Hz, 1H), 2.83 (dt, J = 13.2, 5.6 Hz, 1H), 2.67 (dt, J = 15.8,
4.7 Hz, 1H), 2.40 (dd, J = 16.1, 11.3 Hz, 1H); 13C{1H} NMR (75 MHz, d6-DMSO) δ 145.8, 145.2, 144.6, 142.8,
127.8, 127.0, 125.6, 124.7, 118.7, 115.2, 110.0, 109.8, 57.0, 56.0, 55.7, 55.6, 47.9, 31.4, 29.3; HRMS (FD+): m/z
calculated for C19H21NO4 (M+) 327.1471, found 327.1499.
(S)-(-)-Clarkeanidine 25.18 A solution of norcrassifoline 23 (free base, 63 mg, 0.20 mmol) in anhydrous toluene
(4 mL) was stirred with paraformaldehyde (9.0 mg, 0.30 mmol) at 105 °C for 3 h.
The solvent was evaporated and the isomers were separated by chromatography:
petroleum ether/ethyl acetate 1/1 and ethyl acetate for the ortho isomer clarkeanidine
25 (36.1 mg, 0.11 mmol, 55%), next ethyl acetate/MeOH 97/3 for the para-isomer
caseamine 24 (6.0 mg, 0.018 mmol, 9%). Clarkeanidine (25): mp 177−180 °C
(recrystallized from DCM/petroleum ether), (lit19 178−179 °C); ee 95% (Chiralcel
20
AD column, eluent n-heptane/isopropanol 70:30, flow 1.000 mL/min); [α]D20 −442 (c = 0.1, CHCl3), lit17,18 [α]D
−277 (CHCl3), 1H NMR (300 MHz, CDCl3) δ 6.75 (m, 2H), 6.66 (m, 2H), 5.78 (bs, 2H), 4.24 (d, J = 16.0 Hz, 1H),
3.99 (dd, J = 11.2, 3.5 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.84 (d, J = 16.0 Hz, 1H), 3.72 (dd, J = 16.2, 3.6 Hz,
1H), 3.22-3.12 (m, 1H), 3.12-3.00 (m, 1H), 2.89-2.64 (m, 3H); C{1H} NMR (75 MHz, CDCl3) δ 144.3, 143.8,
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142.5, 141.7, 129.0, 128.8, 124.6, 121.0, 119.4, 108.9, 56.2, 56.2, 56.1, 53.0, 49.1, 32.2, 29.8; HRMS: (FD+): m/z
calculated for C19H22NO4 (M+H)+ 328.1549, found 328.1558.
ASSOCIATED CONTENT
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1H and 13C NMR spectra of all new products and intermediates; chiral HPLC traces of the
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AUTHOR INFORMATION
Corresponding author
E-mail: J.H.vanMaarseveen@uva.nl
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ACKNOWLEDGMENTS
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We thank X. Schaepkens, C. Nieuwendijk, S. Leftin and A. Bond for preliminary experiments. E. Zuidinga and
D. S. Tromp are gratefully acknowledged for mass spectrometric data.
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