Bioinspired Syntheses of the Pyridoacridine Marine Alkaloids Demethyldeoxyamphimedine, Deoxyamphimedine, and Amphimedine

Article abstract of DOI:10.1021/acs.joc.5b02312

Efficient bioinspired syntheses of the biologically active pyridoacridine marine alkaloids demethyldeoxyamphimedine, deoxyamphimedine, and amphimedine are reported. Reaction of styelsamine D, prepared via an optimized route starting from Boc-dopamine, wit

Full text of DOI:10.1021/acs.joc.5b02312

Note
pubs.acs.org/joc
Bioinspired Syntheses of the Pyridoacridine Marine Alkaloids
Demethyldeoxyamphimedine, Deoxyamphimedine, and
Amphimedine
Iman M. Khalil, David Barker, and Brent R. Copp*
School of Chemical Sciences, University of Auckland, 23 Symonds St, Auckland 1010, New Zealand
S
* Supporting Information
ABSTRACT: Efficient bioinspired syntheses of the biologically active pyridoacridine marine alkaloids demethyldeoxyamphi-
medine, deoxyamphimedine, and amphimedine are reported. Reaction of styelsamine D, prepared via an optimized route starting
from Boc-dopamine, with paraformaldehyde afforded demethyldeoxyamphimedine and deoxyamphimedine. Oxidation of the
latter using either K3[Fe(CN)6] or DMSO/conc. HCl gave amphimedine in 8 steps from tryptamine with an overall yield of
14%. The versatility of the method was demonstrated by the synthesis of non-natural ethyl and benzyl congeners of
deoxyamphimedine and amphimedine.
mphimedine (1), reported in 1983 from an Amphimedon
A
sp. sponge, was the first example of a natural product
bearing a new alkaloid skeleton.1 Related dopamine-based
pyridoacridines, encapsulating the 11H-pyrido[4,3,2-mn]-
acridine skeleton, now number greater than 40.2,3 Alkaloids
belonging to this family typically exhibit significant biological
activities, including cytotoxicity.4 For example, of the
pentacyclic pyridoacridine analogues amphimedine (1), neo-
amphimedine (2),5 deoxyamphimedine (3),6 and demethyl-
deoxyamphimedine (4)7 (Figure 1), 1 induces specific
developmental effects in zebrafish embryos,8 2 is cytotoxic
and stimulates topoisomerase II to catenate DNA,5,9,10 and 3
causes damage to DNA via the production of reactive oxygen
species.11 A number of syntheses of amphimedine (1)12−15 and
demethyldeoxyamphimedine (4)16,17 have been reported, all
relying upon either hetero-Diels−Alder or Pd- or Li-metalation
reactions to construct the core skeleton. In the case of
amphimedine, total syntheses have been reported that
incorporate a longest linear sequence of up to 13 steps.
Syntheses of demethyldeoxyamphimedine on the other hand
are considerably shorter with the recent report by Bracher of a
4 step, 6.4% yield sequence being the most efficient to date.17
None of the syntheses, however, can be considered bioinspired
or biomimetic. Several groups have speculated that styelsamine
D (5), itself a natural product isolated from the ascidian
Eusynstyela latericius,18 could be a biosynthetic intermediate to a
large subset of pyridoacridine alkaloids, including 1−4.3,7
Preliminary experiments by Bry et al. observed that addition
of formaldehyde to a marine organism extract that contains
both styelsamine D (5) and demethyldeoxyamphimedine (4)
Figure 1. Structures of marine pyridoacridine alkaloids amphimedine
(1), neoamphimedine (2), deoxyamphimedine (3), demethyldeox-
yamphimedine (4), and styelsamine D (5).
led to the disappearance of the former with time and a
concomitant increase in detectable quantities of the latter.7
Received: October 5, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02312
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The Journal of Organic Chemistry
Note
Scheme 1. Synthesis of Demethyldeoxyamphimedine (4), Deoxyamphimedine (3), and Amphimedine (1)
We report herein an improved synthesis of styelsamine D,
efficient bioinspired conversion of styelsamine D (5) to
demethyldeoxyamphimedine (4) and deoxyamphimedine (3),
and subsequent oxidation of the latter to amphimedine (1).
The versatility of the approach is demonstrated by the synthesis
of non-natural analogues of 1 and 3. In addition, an alternative
route to amphimedine via the anticipated natural product N-
methyl styelsamine D is also demonstrated.
turned to oxidation of deoxyamphimedine. We were interested
in not only achieving oxidation but also discerning whether one
or both of amphimedine (1) or neoamphimedine (2) were the
product(s). The reagent of choice for oxidation of a
methylpyridinium to an N-methylpyridone is K3[Fe(CN)6] in
aq NaOH.14,25,26 In the present study, oxidation of
deoxyamphimedine 3 using alkaline ferricyanide yielded
exclusively amphimedine (1) in 92% yield. A range of other
oxidants were subsequently explored (data not shown), and it
was found that the reaction of deoxyamphimedine (3) in
DMSO/conc. HCl21,22 (9:1) afforded amphimedine in 75%
yield in addition to trace amounts of demethylated starting
material 4. Changing the relative ratio of DMSO/conc. HCl
used in the reaction from 9:1 to 11:1 afforded demethyldeox-
yamphimedine (4) in 14.5% yield and only trace amounts of
amphimedine. This is the first apparent report of N-
methylpyridone formation using such a mild oxidant system.
Neither of these successful oxidants (K3[Fe(CN)6] or DMSO/
conc. HCl) afforded detectable quantities of the isomeric
neoamphimedine (2) natural product.
Among the pyridoacridine alkaloids, deoxyamphimedine (3)
and ascididemin are unique in their ability to induce damage in
DNA via the generation of reactive oxygen species,11,27 whereas
amphimedine appears to be unique in inducing a specific but
mechanistically undefined developmental phenotype in zebra-
fish.8 To facilitate future structure−activity relationship studies,
we investigated whether our new methodology could be used
to synthesize new non-natural ethyl and benzyl analogues of
both deoxyamphimedine and amphimedine (Scheme 2).
Alkylation of N-(3,4-dimethoxyphenethyl)acetamide (12)20
proceeded smoothly to give 13−15 (96−99%), which were
then de-O-methylated (BBr3, CH2Cl2) to give catechols 16−18
(61−99%). Subsequent oxidative coupling with kynuramine
(7) afforded the alkylated styelsamine B analogues 19−21
(10−12%), which upon hydrolysis in aq HCl, gave the
corresponding N-alkyl styelsamine D analogues 22−24 (51−
71%). Ring closure of the anticipated natural product N-
methylstyelsamine D (22)3 using paraformaldehyde in acetic
acid afforded deoxyamphimedine (3) in 91% yield, and the
reaction of ethyl (23) and benzyl (24) analogues of styelsamine
D gave the corresponding deoxyamphimedine analogues 25
and 26 in good yields (83 and 91%, respectively).28 Finally,
oxidation of the latter two products using K3[Fe(CN)6]/NaOH
Skyler and Heathcock have previously reported the develop-
ment of a biomimetic synthesis of styelsamine B (N-acetyl
styelsamine D), where oxidative coupling of N-acetyl dopamine
with kynuramine followed by in situ acid-mediated ring closure
led to the formation of the required pyridoacridine skeleton.19
This procedure required the product to undergo subsequent
acid hydrolysis (MeOH/4 N HCl (1:1), 80 °C, 2 d) to afford
styelsamine D (5).3,20 We have modified this reaction process
to more specifically target the synthesis of styelsamine D by
utilizing tert-butyl 2-(3,4-dihydroxyphenyl) ethylcarbamate
(Boc-dopamine, 6) as starting material and by optimizing the
synthesis of the coupling partner kynuramine (7). The
modified synthesis of kynuramine (7) began by protection of
tryptamine (8) to give carbamate 9 (Scheme 1). Oxidation of
the protected tryptamine (9) yielded oxindole 10,21 which
upon treatment with O2 in basic conditions21,22 afforded
protected kynuramine (11) in quantitative yield. Removal of
the carbamate protecting group gave kynuramine (7) in 81%
yield (Scheme 1). This synthetic route circumvents the use of
ozone as the ring opening reagent and affords kynuramine with
an improved overall yield of 67% (previous overall yield was
57%).19 With kynuramine in hand, coupling of 7 with 623 using
a two-step sequence afforded styelsamine D (5) in 34% yield
(Scheme 1). Reaction of 5 with paraformaldehyde (5 equiv) in
acetic acid24 gratifyingly afforded the two pentacyclic natural
products deoxyamphimedine (3) in 48% yield and demethyl-
deoxyamphimedine (4) in 52% yield. Repeating our reaction
with an increasing number of equivalents of paraformaldehyde
gave a corresponding increase in the yield of 3 vs 4 (9.1 equiv,
58 and 34%, respectively; 15 equiv, 66 and 34%, respectively).
This represents the first reported synthesis of deoxyamphime-
dine and the highest yielding synthesis of demethyldeoxyam-
phimedine reported to date.
With an optimized synthesis of styelsamine D and with the
successful reaction with paraformaldehyde, our attention then
B
DOI: 10.1021/acs.joc.5b02312
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Note
The observed conversion of styelsamine D (5) to both
demethyldeoxyamphimedine and deoxyamphimedine suggests
a mechanism whereby the first mole of formaldehyde achieves a
Pictet−Spengler-type ring closure29 to form 29 (Scheme 3).
Pentacycle 29 can then either undergo in situ oxidation to
demethyldeoxyamphimedine (4) or alternatively react with a
second equivalent of formaldehyde to give 30 with subsequent
tautomerization and oxidation affording deoxyamphimedine
(3). Observation of elevated yields of 3, at the expense of 4,
upon reaction of styelsamine D with increasing equivalents of
paraformaldehyde provides support for this mechanism.
In summary, we have described a versatile bioinspired
approach to the synthesis of the marine natural products
demethyldeoxyamphimedine (4), deoxyamphimedine (3), and
amphimedine (1) and used the methodology to prepare novel
analogues. It is anticipated that this protocol will be useful for
the synthesis of other structurally related biologically active
pyridoacridine natural products.
Scheme 2. Synthesis of Deoxyamphimedine Analogues 25
and 26 and Amphimedine Analogues 27 and 28
EXPERIMENTAL SECTION
■
General Procedures. NMR spectra were recorded at either 500 or
1
400 MHz for H nuclei and 125 or 100 MHz for 13C nuclei. Residual
solvent signals or TMS (when present) were used as reference
(CD3OD: δH 3.31, δC 49.0; CDCl3: δH TMS 0, δC 77.16; TFA-d/
CDCl3: δH TMS 0, δC 77.16; DMSO-d6: δH 2.50, δC 39.52).
Assignments were based on 2D NMR data using standard COSY,
multiplicity edited HSQC, HMBC, and where appropriate NOESY
pulse sequences. ESI-MS (including high resolution) data were
acquired on a micrOTOF Q II mass spectrometer. Analytical
reversed-phase HPLC was run using a C8 column (3 μm, 7 × 33
mm) and eluted with a linear gradient of H2O (0.05% TFA) to MeCN
over 13.5 min at 2 mL/min. Reversed-phase flash column
chromatography was carried out on C2 (40−63 μm) or LH-20 solid
support. Silica gel column chromatography was carried out on silica
media with either 40−63 or 15−40 μm particle sizes. All solvents used
were distilled at analytical grade or better. Chemical reagents used
were purchased from standard chemical suppliers.
Typtamine-Methyl Carbamate (9). A solution of tryptamine
hydrochloride (15 g, 0.090 mol), EtOAc (150 mL), and NaOH (1
N, 95 mL) was degassed and stirred followed by dropwise addition of
methyl chloroformate (11.5 g, 9.40 mL, 0.12 mol) under N2
atmosphere. The mixture was stirred for 45 min at rt and then
washed with water (2 × 50 mL) and dried (MgSO4), and the solvent
was removed under reduced pressure. The crude reaction product was
then dissolved in EtOAc (10 mL) and added to n-hexane (100 mL) to
1
yield 9 as a brown solid (20.4 g, quant.) after filtration. H and 13C
NMR data matched literature values.19
Oxindole (10). A solution of tryptamine methyl carbamate (9, 2.33
g, 10.7 mmol) in glacial acetic acid (50 mL) was added slowly to a
solution of DMSO (2.1 mL) and concd HCl (10.7 mL) and stirred for
1 h and 15 min. The reaction was then poured into saturated aqueous
Na2CO3 (180 mL) and extracted with EtOAc (3 × 80 mL). The
afforded the non-natural amphimedine analogues 27 (85%
yield) and 28 (34% yield).
Scheme 3. Proposed Mechanism for the Conversion of Styelsamine D (5) to Demethyldeoxyamphimedine (4) and
Deoxyamphimedine (3)
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combined organic layers were washed with brine (180 mL) and dried
(MgSO4), and the solvent was removed in vacuo. Purification by silica
gel column chromatography (n-hexane/EtOAc) gave oxindole 10 as a
dark yellow oil (2.1 g, 83%). Rf (100% CH2Cl2) 0.15; (+)-HRESIMS
(C-1), 132.9 (C-3), 131.5 (C-8a), 125.2 (C-4), 124.5 (C-12), 124.2
(C-4a), 122.9 (C-5), 120.9 (C-12c), 49.0 (C-14); (+)-HRESIMS m/z
298.0966 [M] (calcd for C19H12N3O, 298.0975).
Demethyldeoxyamphimedine (4). 1H NMR (TFA-d/CDCl3 (2:1),
400 MHz) δ 9.87 (1H, s, H-9), 9.72 (1H, br s, H-12), 9.63 (1H, br s,
H-5), 9.49 (1H, br s, H-6), 9.40 (1H, br s, H-11), 9.05 (1H, d, J = 7.7
Hz, H-4), 8.80 (1H, d, J = 7.7 Hz, H-1), 8.47 (1H, t, J = 7.7 Hz, H-3),
8.33 (1H, t, J = 7.7 Hz, H-2); 13C NMR (TFA-d/CDCl3 (2:1), 100
MHz) δ 173.7 (C-8), 150.6 (C-12a), 148.0 (C-13a), 146.5 (C-4b),
146.4 (C-11), 144.1 (C-9), 143.4 (C-12b), 141.5 (C-6), 138.2 (C-2),
138.1 (C-7a), 135.4 (C-3), 134.9 (C-1), 128.7 (C-8a), 126.8 (C-5),
126.2 (C-4), 125.0 (C-12), 121.3 (C-4a), signal due to C-12c was
obscured by TFA-d peaks; 1H NMR (CDCl3, 500 MHz) δ 9.72 (1H, s,
H-9), 9.38 (1H, d, J = 5.4 Hz, H-6), 9.12 (1H, d, J = 5.5 Hz, H-12),
8.84 (1H, d, J = 5.5 Hz, H-11), 8.71 (1H, d, J = 5.4 Hz, H-5), 8.68
(1H, dd, J = 8.4, 1.3 Hz, H-4), 8.43 (1H, dd, J = 8.4, 1.3 Hz, H-1), 8.01
(1H, dt, J = 8.4, 1.3 Hz, H-2), 7.90 (1H, dt, J = 8.4, 1.3 Hz, H-3); 13C
NMR (CDCl3, 125 MHz) δ 154.8, 150.7, 150.5, 147.3, 147.0, 145.7,
142.2, 138.3, 132.2, 132.0, 130.0, 126.6, 123.0, 122.4, 120.0, 119.2,
118.5 (one resonance not observed); (+)-HRESIMS m/z 306.0647
[M + Na]+ (calcd for C18H9N3NaO, 306.0638).
1
m/z 235.1077 [M + H]+ (calcd for C12H15N2O3, 235.1077). H and
13C NMR data matched literature values.21
Kynuramine-Methyl Carbamate (11). Oxygen was bubbled into a
stirred solution of the oxindole 10 (0.2 g, 0.85 mmol) in 1 N NaOH
(10 mL). The resulting mixture was stirred for a further 3 h and 45
min at rt after which 10% HCl was added to adjust the pH to 7. The
mixture was then extracted with EtOAc (3 × 20 mL); the combined
organic extracts were dried over MgSO4, and the solvent was removed
under reduced pressure to yield 11 as a yellow solid (0.19 g, quant.).
1H and 13C NMR data matched literature values.19
Kynuramine Dihydrobromide (7). A solution of 11 (0.19 g, 0.65
mmol) in HBr in acetic acid (7 mL) was stirred and heated at 80 °C
under N2 atmosphere overnight. After the solution was cooled to rt,
THF was added (15 mL), and the mixture was stirred at 0 °C for 30
min. The brown solid was then triturated (THF) to yield 7 as an off-
white solid (0.19 g, 81.1%). 1H and 13C NMR data matched literature
values.19
N-(3,4-Dimethoxyphenethyl)acetamide (12). A solution of 2-(3,4-
dimethyoxyphenyl)ethyl amine (0.2 g, 0.19 mL, 1.10 mmol) in Et3N
(0.24 mL, 0.20 g, 1.99 mmol) and acetic anhydride (0.38 mL, 0.41 g,
3.97 mmol) was stirred at rt under N2 atmosphere for 45 min.
Dichloromethane (5 mL) was then added, and the mixture was washed
with H2O (10 mL). The organic phase was then dried (MgSO4), and
the solvent was removed under reduced pressure to afford 12 as a dark
Amphimedine (1). A solution of NaOH (1.02 mg, 0.025 mmol) in
water (200 μL) and a solution of potassium ferricyanide (4.18 mg,
0.013 mmol) in water (200 μL) were added simultaneously to a stirred
solution of deoxyamphimedine (3, 2.61 mg, 6.4 μmol) in water (500
μL) at 0 °C over a period of 10 min. After the dropwise addition, the
reaction mixture was stirred for 25 min after which it was diluted with
water (1 mL) and extracted with CH2Cl2 (5 × 3 mL). The combined
organic extracts were dried (MgSO4), and the solvent was removed in
vacuo. The product mixture was purified using silica gel column
chromatography (CH2Cl2/MeOH, 9:1) to give amphimedine (1) as a
bright yellow powder (1.82 mg, 92%). Alternatively, deoxyamphime-
dine (1.41 mg, 3.4 μmol) was dissolved in DMSO (90 μL), and concd
HCl (10 μL) was added. The solution was stirred at rt for 2 h. The
solution was then neutralized by the addition of sat. aq NaHCO3 and
extracted with CH2Cl2 (5 × 3 mL), and the crude product was purified
by LH-20 column chromatography (MeOH) to give amphimedine (1)
1
yellow oil (0.24 g, 97.6%). H and 13C NMR data matched literature
values.20
N-Boc-Dopamine (6). Boc2O (1.09 g, 5.00 mmol) was added to a
solution of dopamine hydrochloride (0.86 g, 4.53 mmol) in a mixture
of THF (9.4 mL) and sat. aq NaHCO3 (5.6 mL). The reaction mixture
was stirred at rt for 2 h after which the aqueous layer was extracted
with EtOAc (3 × 10 mL). The combined organic extracts were washed
with brine, dried over MgSO4, and concentrated under reduced
pressure to yield 6 as a white solid (1.15 g, quant.). 1H and 13C NMR
data matched literature values.23
1
(1.07 mg, 75%). Rf (CH2Cl2/MeOH, 9:1) 0.21; H NMR (TFA-d/
Styelsamine D (5). Kynuramine dihydrobromide (7) (0.10 g, 0.41
mmol) was added to a stirred solution of tert-butyl 2-(3,4-
dihydroxyphenyl)ethylcarbamate4 (6, 0.13 g, 0.39 mmol) in MeOH/
acetic acid (2:1, 6 mL) under a N2 atmosphere followed by the
addition of CeCl3·7H2O (0.022 g, 0.054 mmol) and Ag2O (0.20 g,
0.99 mmol). The mixture was stirred at 40 °C for 1 h and 30 min after
which the solution was filtered through Celite and added dropwise to a
solution of 6 N HCl (15 mL) at 90 °C. The solution was stirred for a
further 2 h, and then the solvent was removed in vacuo. The product
mixture was purified using C2 reversed-phase chromatography
(MeOH/H2O/TFA) to give styelsamine D ditrifluoroacetate as a
purple oil (0.068 g, 34%). 1H, 13C, and HRMS data agreed with
literature values.20
CDCl3 (2:1), 400 MHz) δ 9.39 (1H, s, H-9), 9.30 (1H, d, J = 5.5 Hz,
H-12), 9.10 (2H, m, H-6, 11), 8.88 (1H, br s, H-5), 8.64 (1H, d, J =
7.56 Hz, H-4), 8.35 (1H, d, J = 7.6 Hz, H-1), 8.35 (1H, t, J = 7.6 Hz,
1
H-2), 8.18 (1H, t, J = 7.7 Hz, H-3), 3.98 (3H, s, H3-14); H NMR
(CDCl3, 400 MHz) δ 9.30 (1H, d, J = 5.5 Hz, H-6), 8.80 (1H, s, H-9),
8.77−8.63 (2H, m, H-4, 5), 8.37 (1H, dd, J = 8.1, 1.1 Hz, H-1), 8.06
(1H, s, H-12), 7.99 (1H, dt, J = 8.1, 1.1 Hz, H-2), 7.87 (1H, dt, J = 8.1,
1.1 Hz, H-3), 3.80 (3H, s, H3-14); 13C NMR (TFA-d/CDCl3 (2:1),
100 MHz) δ 172.8 (C-8), 165.6 (C-11), 147.7 (C-13a), 147.3 (C-9),
145.8 (C-4b), 145.3 (C-12b), 143.5 (C-12a), 139.5 (C-6, C-7), 137.4
(C-2), 133.5 (C-1), 133.0 (C-3), 125.3 (C-4), 124.9 (C-5), 120.4 (C-
4a), 118.7 (C-12c), 114.9 (C-12), 113.5 (C-12c), 40.0 (C-14);
(+)-HRESIMS m/z 314.0931 [M + H]+ (calcd for C19H12N3O2,
314.0924).
General Procedure A: Alkylation of N-(3,4-Dimethoxyphenethyl)-
acetamide (12). The relevant alkyl halide (2−4 equiv) is added
dropwise to a solution of N-(3,4-dimethoxyphenethyl)acetamide (1
equiv) and sodium hydride (2 equiv) in THF/DMF (10:1, 5 mL). The
reaction was allowed to stir at rt under N2 atmosphere for 10 min after
which the mixture was heated at reflux overnight. The solvent was then
removed in vacuo, and the product mixture was dissolved in EtOAc
and washed with sat. aq Na2S2O3 and then dried (MgSO4). The
solvent was then removed in vacuo to yield the alkylated product.
General Procedure B: De-O-methylation of N-Alkyl-dimethox-
yphenethylacetamides. To a stirred solution of the alkylated
acetamide (1 equiv) in CH2Cl2 was added a solution of BBr3 (9
equiv) in CH2Cl2 dropwise at 0 °C under a N2 atmosphere. The
mixture was stirred for 5−6 h after which MeOH was added followed
by washing with brine and water. The aqueous layer was extracted with
EtOAc, and the organic extract was dried (MgSO4) followed by
removal of the solvent in vacuo to yield the demethylated product.
Deoxyamphimedine (3) and Demethyldeoxyamphimedine (4).
Paraformaldehyde (4.79 mg, 0.16 mmol) was added to a solution of
styelsamine D ditrifluoroacetate (16.1 mg, 0.032 mmol) in acetic acid
(2 mL) and stirred for 5 h at 60 °C and then left stirring overnight at
rt. The acetic acid was then removed in vacuo, and the product
mixture was purified using Sephadex LH-20 column chromatography
(MeOH/TFA) to give, in order of elution, deoxyamphimedine (3,
13.1 mg, 48%) as a brown/yellow oil and demethyldeoxyamphimedine
(4, 9.1 mg, 52%) as a brown oil. Repeating the reaction in the presence
of increasing equivalents of paraformaldehyde gave 3 (58%) and 4
(34%) with 9.1 equiv of paraformaldehyde and 3 (66%), 4 (34%) with
15 equiv of paraformaldehyde.
1
Deoxyamphimedine (3). H NMR (CD3OD, 400 MHz) δ 9.88
(1H, s, H-9), 9.42 (1H, d, J = 5.5 Hz, H-12), 9.33−9.25 (2H, m, H-6,
11), 9.08 (1H, br s, H-5), 8.93 (1H, d, J = 7.56 Hz, H-4), 8.47 (1H, d,
J = 7.6 Hz, H-1), 8.11 (1H, t, J = 7.6 Hz, H-2), 8.04 (1H, t, J = 7.7 Hz,
H-3), 4.66 (3H, s, H3-14); 13C NMR (CD3OD, 100 MHz) δ 179.2 (C-
8), 151.4 (C-6), 149.4 (C-11), 149.4 (C-12a), 147.9 (C-9), 147.2 (C-
7a), 146.6 (C-13a), 145.4 (C-12b), 139.8 (C-4b), 134.0 (C-2), 133.3
D
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General Procedure C: Preparation of N-Alkyl Analogues of
Styelsamine B. Kynuramine dihydrobromide (7, 1.05 equiv) was
added to a stirred solution of the relevant N-dihydroxyphenylethyl-N-
alkylacetamide (1 equiv) in MeOH-HOAc (2:1, 5 mL) under N2
atmosphere followed by the addition of CeCl3·7H2O (0.15 equiv) and
Ag2O (2.2 equiv). The mixture was stirred at 40 °C for 2 h after which
the solution was filtered through Celite and added dropwise to a
solution of 6 N HCl (20 mL) at 90 °C. The solution was stirred for a
further 30 min and then dried in vacuo. The product mixture was
purified using C2 reversed-phase flash (MeOH/H2O/0.05% TFA) and
Sephadex LH-20 column chromatography (MeOH/0.05% TFA) to
yield styelsamine B analogues as the TFA salts.
General Procedure D: Preparation of N-Alkyl Analogues of
Styelsamine D. A solution of N-alkyl styelsamine B and 6 N HCl was
stirred for 30−50 h at 80 °C. Concentration of the reaction mixture
under reduced pressure was followed by purification using C18
reversed-phase flash column chromatography (MeOH/H2O/0.05%
TFA) to yield the styelsamine D analogues as di-TFA salts.
General Procedure E: Synthesis of N-alkyl Analogues of
Demethyldeoxyamphimedine. Paraformaldehyde (5 equiv) was
added to a solution of N-alkyl-styelsamine D (1 equiv) in acetic acid
and stirred for 5−6 h at 60 °C and then left stirring overnight at rt.
The acetic acid was then removed in vacuo, and the product mixture
was purified using Sephadex LH-20 column chromatography (MeOH
+ 0.05% TFA) to yield N-alkyl analogues of demethyldeoxyamphi-
medine.
General Procedure F: Synthesis of N-Alkyl Analogues of
Demethylamphimedine. A solution of NaOH (4 equiv) in water
and a solution of potassium ferricyanide (2 equiv) in water were added
dropwise simultaneously to a stirred solution of N-alkyl-demethyl-
deoxyamphimedine in water at 0 °C over a period of 10 min. After the
addition, the reaction mixture was stirred for 20 min after which it was
diluted with water and extracted with CH2Cl2. The combined organic
layers were dried (MgSO4), and the solvent was removed in vacuo.
The product mixture was purified using silica gel column
chromatography (CH2Cl2/MeOH, 9:1) to yield N-alkyl analogues of
demethylamphimedine.
(CDCl3, 400 MHz) δ 6.68 (1H, d, J = 8.0 Hz, H-8), 6.64−6.63 (1H,
m, H-5), 6.52−6.50 (1H, m, H-9), 3.53−3.50 (2H, m, H2-2), 2.89
(3H, s, H3-10), 2.71 (2H, t, J = 6.7 Hz, H2-3), 1.76 (3H, s, H3-12); 13
C
NMR (CDCl3, 100 MHz) δ 173.5 (C-11), 146.2 (C-6), 144.8 (C-7),
131.3 (C-4), 121.1 (C-9), 116.9 (C-5), 116.4 (C-8), 53.8 (C-2), 34.6
(C-3), 33.79 (C-10), 20.8 (C-12); (+)-HRESIMS m/z 232.0948 [M +
1
Na]+ (calcd for C11H15NNaO3, 232.0944). H and 13C signals could
not be assigned to specific rotamers.
N-(3,4-Dimethoxyphenethyl)-N-ethylacetamide (14). Using gen-
eral procedure A, N-(3,4-dimethoxyphenethyl)acetamide (12, 0.46 g,
1.80 mmol), ethyl bromide (0.39 g, 0.27 mL, 3.6 mmol), and sodium
hydride (0.14 g, 3.6 mmol) afforded 14 as a pale yellow oil (0.52 g,
quantitative yield) in a mixture of rotamers. Rf (30% EtOAc/Hex)
0.12; IR (ATR) νmax 2935, 1623, 1515, 1420, 1261, 1236 cm−1.
Rotamer 1: 1H NMR (CDCl3, 500 MHz) δ 6.82 (1H, d, J = 7.8 Hz, H-
8), 6.70 (1H, dd, J = 7.8, 2.0 Hz, H-9), 6.66 (1H, d, J = 2.0 Hz, H-5),
3.88 (3H, s, H3-14), 3.86 (3H, s, H3-15), 3.45 (2H, t, J = 7.3 Hz, H2-
2), 3.40 (2H, q, J = 7.3 Hz, H2-10), 2.79−2.76 (2H, m, H2-3), 1.91
(3H, s, H3-13), 1.16−1.11 (3H, m, H3-11); 13C NMR (CDCl3, 125
MHz) δ 170.2 (C-12), 149.2 (C-6), 148.0 (C-7), 130.9 (C-4), 120.9
(C-9), 112.2 (C-5), 111.4 (C-8), 56.0 (C-13, 14), 50.2 (C-2), 40.5 (C-
10), 35.1 (C-3), 21.6 (C-13), 13.0 (C-11). Rotamer 2: 1H NMR
(CDCl3, 500 MHz) δ 6.80−6.78 (1H, m, H-5), 6.77−6.74 (2H, m, H-
8, 9), 3.88 (3H, s, H3-14), 3.86 (3H, s, H3-15), 3.50 (2H, t, J = 7.4 Hz,
H2-2), 3.20 (2H, q, J = 7.1 Hz, H2-10), 2.82−2.79 (2H, m, H2-3), 2.10
(3H, s, H3-13), 1.16−1.11 (3H, m, H3-11); 13C NMR (CDCl3, 125
MHz) δ 170.1 (C-12), 149.0 (C-6), 147.6 (C-7), 132.1 (C-4), 120.8
(C-9), 112.1 (C-5), 111.6 (C-8), 56.0 (C-13, 14), 47.8 (C-2), 44.1 (C-
10), 33.9 (C-3), 21.5 (C-13), 14.1 (C-11); (+)-HRESIMS m/z
274.1414 [M + Na]+ (calcd for C14H21NNaO3, 274.1414). 1H and 13
C
signals could not be assigned to specific rotamers.
N-(3,4-Dihydroxyphenethyl)-N-ethylacetamide (17). Using gen-
eral procedure B, N-(3,4-dimethoxyphenethyl)-N-ethylacetamide (14,
0.38 g. 1.5 mmol) and BBr3 (3.0 g, 12.1 mmol. 1.10 mL) afforded 17
as a pale brown gum (0.33 g, 98% yield) in a mixture of rotamers. IR
(ATR) νmax 3179, 2977, 1588, 1441, 1280 cm−1. Rotamer 1: 1H NMR
(CD3OD, 500 MHz) δ 6.71−6.67 (1H, m, H-8), 6.66−6.62 (1H, m,
H-5), 6.54−6.49 (1H, m, H-9), 3.48 (2H, t, J = 7.1, H2-2), 3.36 (2H, q,
J = 7.2 Hz, H2-10), 2.72 (2H, obscured, H2-3), 2.08 (3H, s, H3-13),
1.11−1.08 (3H, m, H3-11); 13C NMR (CDCl3, 125 MHz) δ 173.1 (C-
12), 146.5 (C-6)f, 145.1 (C-7), 131.3 (C-4), 121.3 (C-9), 117.1 (C-5),
116.5 (C-8), 51.4 (C-2), 41.7 (C-10), 35.2 (C-3), 21.2 (C-13), 12.9
(C-11). Rotamer 2: 1H NMR (CD3OD, 500 MHz) δ 6.71−6.67 (1H,
m, H-8), 6.66−6.62 (1H, m, H-5), 6.54−6.49 (1H, m, H-9), 3.44 (2H,
t, J = 6.8, H2-2), 3.25 (2H, q, J = 7.2 Hz, H2-10), 2.67 (2H, obscured,
H2-3), 1.81 (3H, s, H3-13), 1.14−1.11 (3H, m, H3-11); 13C NMR
(CDCl3, 125 MHz) δ 172.8 (C-12), 146.3 (C-6), 144.8 (C-7), 132.1
(C-4), 121.1 (C-9), 116.9 (C-5), 116.4 (C-8), 49.1 (C-2), 45.2 (C-
10), 34.3 (C-3), 21.2 (C-13), 14.0 (C-11); (+)-HRESIMS m/z
N-(3,4-Dimethoxyphenethyl)-N-methylacetamide (13). Using
general procedure A, N-(3,4-dimethoxyphenethyl)acetamide (12, 0.3
g, 1.34 mmol), methyl iodide (0.67 g, 0.29 mL, 4.7 mmol), and sodium
hydride (64.5 mg, 2.69 mmol) afforded 13 as a yellow oil (0.31 g,
97%) in a 1:1 mixture of rotamers. Rf (100% CH2Cl2) 0.17; IR (ATR)
νmax 2933, 1514, 1626, 1261, 1236 cm−1. Rotamer 1: 1H NMR
(CDCl3, 400 MHz) δ 6.81 (1H, d, J = 8.2 Hz, H-8), 6.76 (1H,
obscured, H-5), 6.69 (1H, dd, J = 1.9, 8.2 Hz, H-9), 3.86 (3H, s, H3-
13), 3.85 (3H, s, H3-14), 3.49 (2H, t, J = 7.0 Hz, H2-2), 2.93 (3H, s,
H3-10), 2.81−2.78 (2H, m, H2-3), 1.84 (3H, s, H3-12); 13C NMR
(CDCl3, 100 MHz) δ 170.5 (C-11), 148.9 (C-6), 147.7 (C-7), 130.6
(C-4), 120.5 (C-9), 111.9 (C-5), 111.4 (C-8), 55.7 (C-13, 14), 52.4
1
1
224.1283 [M + H]+ (calcd for C12H18NO3, 224.1281). H and 13C
(C-2), 34.0 (C-3), 33.1 (C-10), 20.7 (C-12). Rotamer 2: H NMR
(CDCl3, 400 MHz) δ 6.80 (1H, d, J = 7.9 Hz, H-8), 6.75 (1H, dd, J =
7.9, 2.0 Hz, H-9), 6.66 (1H, d, J = 2.0 Hz, H-9), 3.86 (3H, s, H3-13),
3.84 (3H, s, H3-14), 3.56 (2H, t, J = 7.8 Hz, H2-2), 2.89 (2H, s, H3-
10), 2.78−2.76 (2H, m, H2-3), 2.06 (3H, s, H3-12); 13C NMR
(CDCl3, 100 MHz) δ 170.3 (C-11), 148.7 (C-6), 147.3 (C-7), 131.5
(C-4), 120.6 (C-9), 111.8 (C-5), 111.2 (C-8), 55.7 (C-13, 14), 49.5
(C-2), 36.6 (C-10), 33.1 (C-3), 21.7 (C-12); (+)-HRESIMS m/z
signals could not be assigned to specific rotamers.
N-(3,4-Dimethoxyphenethyl)-N-benzylacetamide (15). Using gen-
eral procedure A, N-(3,4-dimethoxyphenethyl)acetamide (12, 0.54 g,
2.42 mmol), benzyl bromide (0.83 g, 0.58 mL, 4.8 mmol), and sodium
hydride (0.19 g, 4.8 mmol) afforded 15 as a pale yellow oil (0.73 g,
96%) in a mixture of rotamers. Rf (50% EtOAc/Hex) 0.16; IR (ATR)
νmax 2934, 1634, 1515, 1419, 1261, 1027 cm−1. Rotamer 1: H NMR
1
260.1262 [M + Na]+ (calcd for C13H19NNaO3, 260.1257). 1H and 13
C
(CDCl3, 500 MHz) δ 7.37−7.34 (2H, m, H-17, 19), 7.31−7.27 (2H,
m, H-16, 20), 7.26−7.23 (1H, m, H-18), 6.81−6.76 (1H, m, H-8),
6.65 (1H, dd, J = 8.5, 1.9 Hz, H-9), 6.58 (1H, d, J = 1.9 Hz, H-5), 4.60
(2H, s, H2-14), 3.85 (6H, s, H3-12, 13), 3.42 (2H, t, J = 7.2 Hz, H2-2),
2.74 (2H, t, J = 7.2 Hz, H2-3), 2.02 (3H, s, CH3-11); 13C NMR
(CDCl3, 125 MHz) δ 170.8 (C-10), 149.0 (C-6), 148.0 (C-7), 137.8
(C-15), 130.9 (C-4), 129.0 (C-17, 18), 128.3 (C-16, 20), 127.7 (C-
18), 120.8 (C-9), 112.1 (C-5), 111.6 (C-8), 56.0 (C-12, 13), 49.7 (C-
2), 48.3 (C-14), 33.7 (C-3), 21.4 (C-11). Rotamer 2: 1H NMR
(CDCl3, 500 MHz) δ 7.37−7.34 (2H, m, H-17, 19), 7.26−7.23 (1H,
m, H-18), 7.13 (2H, d, J = 7.6 Hz, H-16, 20), 6.81−6.76 (1H, m, H-8),
6.72−6.69 (2H, m, H-5, 9), 6.58 (1H, d, J = 1.9 Hz, H-5), 4.36 (2H, s,
H2-14), 3.85 (6H, s, OCH3-12, 13), 3.56 (2H, t, J = 7.3 Hz, H2-2),
signals could not be assigned to specific rotamers.
N-(3,4-Dihydroxyphenethyl)-N-methylacetamide (16). Using gen-
eral procedure B, N-(3,4-dimethoxyphenethyl)-N-methylacetamide
(13, 50.0 mg. 0.21 mmol) and BBr3 (0.48 g, 1.90 mmol. 0.18 mL)
afforded 16 as a yellow oil (27.0 mg, 61%) in a 1:1 mixture of
rotamers. IR (ATR) νmax 3187, 1583, 1440, 1408, 1233, 1113 cm−1.
Rotamer 1: 1H NMR (CDCl3, 400 MHz) δ 6.70 (1H, d, J = 8.1 Hz, H-
8), 6.65−6.64 (1H, m, H-5), 6.54−6.52 (1H, m, H-9), 3.50−3.46 (2H,
m, H2-2), 2.91 (3H, s, H3-10), 2.66 (2H, t, J = 7.1 Hz, H2-3), 2.04 (3H,
s, H3-12); 13C NMR (CDCl3, 100 MHz) δ 173.2 (C-11), 146.4 (C-6),
145.1 (C-7), 131.9 (C-4), 121.2 (C-9), 117.1 (C-5), 116.5 (C-8), 51.1
1
(C-2), 37.3 (C-10), 33.84 (C-3), 21.7 (C-12). Rotamer 2: H NMR
E
DOI: 10.1021/acs.joc.5b02312
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
2.80 (2H, t, J = 7.3 Hz, H2-3), 2.12 (3H, s, CH3-11); 13C NMR
(CDCl3, 125 MHz) δ 171.0 (C-10), 149.2 (C-6), 147.6 (C-7), 136.9
(C-15), 131.9 (C-4), 129.0 (C-17, 18), 127.5 (C-18), 126.4 (C-16,
20), 120.8 (C-9), 112.0 (C-5), 111.4 (C-8), 56.0 (C-12, 13), 52.9 (C-
14), 48.4 (C-2), 34.6 (C-3), 22.0 (C-11); (+)-HRESIMS m/z
143.3 (C-2), 142.3 (C-7a), 137.9 (C-11), 136.1 (C-6), 129.9 (C-8a),
127.2 (C-11a), 126.0 (C-4), 123.8 (C-5), 122.6 (C-10), 121.5 (C-
11b), 119.0 (C-7), 116.8 (C-9), 115.2 (C-3b), 105.5 (C-3), 46.4 (C-
16), 46.3 (C-13), 31.5 (C-12), 21.2 (C-15), 14.7 (C-17);
(+)-HRESIMS m/z 348.1716 [M + H]+ (calcd for C21H22N3O2,
348.1707).
1
336.1563 [M + Na]+ (calcd for C19H23NNaO3, 336.1570). H and
13C signals could not be assigned to specific rotamers.
N-Benzyl-styelsamine B (21). Using general procedure C, kynur-
amine dihydrobromide (7, 0.12 g, 0.37 mmol), N-(3,4-dihydrox-
yphenethyl)-N-benzylacetamide (18, 0.10 g, 0.35 mmol), CeCl3·7H2O
(0.020 g, 0.05 mmol), and Ag2O (0.18 g, 0.77 mmol) afforded 21 as a
purple oil (TFA salt, 20.5 mg, 11% yield). Rt = 9.53 min; IR (ATR)
N-(3,4-Dihydroxyphenethyl)-N-benzylacetamide (18). Using gen-
eral procedure B, N-(3,4-dimethoxyphenethyl)-N-benzylacetamide
(15, 0.41 g. 1.31 mmol) and BBr3 (2.62 g, 10.0 mmol. 0.97 mL)
afforded 18 as a white gum (0.36 g, 97%) in a mixture of rotamers. IR
(ATR) νmax 3207, 1596, 1440, 1419, 1363, 1194 cm−1. Rotamer 1: 1H
NMR (CDCl3, 500 MHz) δ 7.41−7.34 (2H, m, H-15, 17), 7.29−7.25
(1H, m, H-16), 7.16 (2H, d, J = 8.0 Hz H-14, 18), 6.72−6.66 (1H, m,
H-8), 6.62−6.59 (1H, m, H-5), 6.51−6.45 (1H, m, H-9), 4.43 (2H, s,
H2-12), 3.46 (2H, t, J = 7.5 Hz, H2-2), 2.66 (2H, t, J = 7.5 Hz, H2-3),
1.94 (3H, s, CH3-11); 13C NMR (CDCl3, 125 MHz) δ 173.6 (C-10),
146.5 (C-6), 145.1 (C-7), 138.2 (C-13), 132.0 (C-4), 129.9 (C-15,
17), 128.6 (C-16), 127.7 (C-14, 18), 121.3 (C-9), 117.0 (C-5), 116.5
(C-8), 53.8 (C-12), 49.8 (C-2), 34.1 (C-3), 21.2 (C-11). Rotamer 2:
1H NMR (CDCl3, 500 MHz) δ 7.34−7.30 (2H, m, H-15, 17), 7.29−
7.25 (1H, m, H-16), 7.23−7.22 (2H, m, H-14, 18), 6.72−6.66 (1H, m,
H-8), 6.62−6.59 (1H, m, H-5), 6.51−6.45 (1H, m, H-9), 4.57 (2H, s,
H2-12), 3.43 (2H, t, J = 7.2 Hz, H2-2), 2.68 (2H, t, J = 7.2 Hz, H2-3),
2.11 (3H, s, CH3-11); 13C NMR (CDCl3, 125 MHz) δ 173.6 (C-10),
146.3 (C-6), 144.8 (C-7), 138.8 (C-13), 131.3 (C-4), 129.6 (C-15,
17), 129.0 (C-14, 18), 128.4 (C-16), 121.1 (C-9), 116.9 (C-5)j, 116.4
(C-8), 51.0 (C-2), 49.0 (C-12), 34.8 (C-3), 21.8 (C-11);
(+)-HRESIMS m/z 308.1253 [M + Na]+ (calcd for C17H19NNaO3,
308.1257). 1H and 13C signals could not be assigned to specific
rotamers.
1
νmax 3423, 2949, 1661, 1582, 1250, 1130 cm−1; H NMR (CD3OD,
500 MHz) δ 7.93 (1H, br s, H-2), 7.89−7.83 (1H, m, H-4), 7.58−7.52
(1H, m, H-6), 7.53−7.47 (1H, m, H-7), 7.42 (2H, t, J = 7.7, H-19, 21),
7.35 (1H, d, J = 7.7 Hz, H-20), 7.30 (2H, d, J = 7.7 Hz, H-18, 22)
7.19−7.12 (2H, m, H-3, 5), 7.04 (1H, s, H-10), 4.72 (2H, s, H2-16),
3.36−3.31 (2H, m, H2-13), 2.74−2.64 (2H, m, H2-12), 2.30 (3H, s,
H3-15); 13C NMR (CD3OD, 125 MHz) δ 174.7 (C-14), 150.9 (C-3a),
143.3 (C-2), 142.3 (C-7a), 138.0 (C-11)a, 137.9 (C-17)a, 136.2 (C-6),
130.1 (C-19, 21), 129.9 (C-8a), 129.0 (C-20), 128.2 (C-18, 22), 127.3
(C-11a), 126.0 (C-4), 123.9 (C-5), 122.5 (C-10), 121.5 (C-11b),
119.0 (C-7), 116.7 (C-9), 115.3 (C-3b), 105.5 (C-3), 54.8 (C-16),
47.0 (C-13), 31.0 (C-12), 21.8 (C-15); (+)-HRESIMS m/z 410.1859
[M + H]+ (calcd for C26H24N3O2, 410.1863).
N-Methyl-styelsamine D (22). Using general procedure D, N-
methyl-styelsamine B (19, 15.1 mg, 0.03 mmol) and 6 N HCl (8 mL)
afforded 22 as a purple oil (bis-TFA salt, 7.07 mg, 41% [71% yield
based on recovered starting material]). Rt = 7.01 min; IR (ATR) νmax
1
3098, 1677, 1619, 1582, 1197, 1132 cm−1; H NMR (CD3OD, 500
MHz) δ 8.19 (1H, d, J = 6.6 Hz, H-2), 8.12 (1H, d, J = 8.2 Hz, H-4),
7.90 (1H, d, J = 8.2 Hz, H-7), 7.67 (1H, t, J = 8.2 Hz, H-6), 7.53 (1H,
d, J = 6.3 Hz, H-3), 7.49 (1H, s, H-10), 7.26 (1H, t, J = 8.2 Hz, H-5),
3.41−3.36 (2H, m, H2-12), 3.27−3.31 (2H, m, H2-13), 2.78 (3H, s,
H3-15); 13C NMR (CD3OD, 125 MHz) δ 151.5 (C-3a), 143.9 (C-2),
142.7 (C-7a), 138.6 (C-11), 136.4 (C-6), 130.3 (C-8a), 128.7 (C-11a),
126.3 (C-4), 124.2 (C-5), 122.8 (C-10), 122.2 (C-11b), 119.2 (C-7),
115.7 (C-3b), 114.4 (C-9), 106.5 (C-3), 49.0 (C-13), 33.8 (C-15),
28.7 (C-12); 1H NMR (DMSO-d6, 500 MHz) δ 10.98 (2H, br s, NH-
8), 8.70 (2H, br s, NH-14), 8.32 (1H, d, J = 6.3 Hz, H-2), 8.25 (1H, d,
J = 8.2 Hz, H-4), 7.81 (1H, d, J = 8.7 Hz, H-7), 7.71 (1H, t, J = 8.7 Hz,
H-6), 7.62 (1H, d, J = 6.3 Hz, H-3), 7.49 (1H, s, H-10), 7.25 (1H, t, J
= 8.2 Hz, H-5), 3.28 (2H, t, J = 6.9 Hz, H2-12), 3.22−3.18 (2H, m, H2-
13), 2.62 (3H, t, J = 4.7 Hz, H3-15); 13C NMR (DMSO-d6, 125 MHz)
δ 150.0 (C-3a), 143.6 (C-2), 141.1 (C-7a), 137.1 (C-11), 135.0 (C-6),
128.5 (C-8a), 126.8 (C-11a), 125.5 (−4), 122.7 (C-5), 121.9 (C-10),
120.6 (C-11b), 117.9 (C-7), 113.6 (C-9), 115.5 (C-3b), 105.4 (C-3),
47.0 (C-13), 32.7 (C-15), 27.1 (C-12); (+)-HRESIMS m/z 292.1448
[M + H]+ (calcd for C18H18N3O, 292.1444).
N-Ethyl-styelsamine D (23). Using general procedure D, N-ethyl-
styelsamine B (20, 11.9 mg, 0.03 mmol) and 6 N HCl (8 mL) afforded
23 as a purple oil (bis-TFA salt, 3.95 mg, 29% [51% based on
recovered starting material]). Rt = 7.47 min; IR (ATR) νmax 3403,
2949, 1672, 1583, 1250, 1132 cm−1; 1H NMR (CD3OD, 500 MHz) δ
8.10 (1H, br s, H-2), 8.02 (1H, d, J = 7.8 Hz, H-4), 7.68 (1H, d, J = 7.8
Hz, H-7), 7.63 (1H, t, J = 7.8 Hz, H-6), 7.42−4.38 (2H, m, H-3, 10),
7.22 (1H, t, J = 7.8 Hz, H-5), 3.28−3.24 (4H, m, H2-12, 13), 3.12 (2H,
q, J = 7.3 Hz, H2-15), 1.34 (3H, t, J = 7.3 Hz, H3-16); 13C NMR
(CD3OD, 125 MHz) δ 151.3 (C-3a), 143.7 (C-2), 142.5 (C-7a), 138.6
(C-11), 136.4 (C-6), 130.0 (C-8a), 128.4 (C-11a), 126.1 (C-4), 124.2
(C-5), 122.8 (C-10), 122.0 (C-11b), 119.1 (C-7), 115.5 (C-3b), 114.5
(C-9), 106.2 (C-3), 47.1 (C-13), 44.3 (C-13), 28.7 (C-12), 11.4 (C-
16); (+)-HRESIMS m/z 306.1597 [M + H]+ (calcd for C19H20N3O,
306.1601).
N-Methyl-styelsamine B (19). Using general procedure C, kynur-
amine dihydrobromide (7, 0.11 g, 0.35 mmol), N-(3,4-dihydrox-
yphenethyl)-N-methylacetamide (16, 0.075 g, 0.33 mmol), CeCl3·
7H2O (0.019 g, 0.005 mmol), and Ag2O (0.17 g, 0.73 mmol) afforded
19 as a purple oil (TFA salt, 15.1 mg, 10% yield). Rt = 8.27 min; IR
(ATR) νmax 3098, 1677, 1619, 1582, 1197, 1132 cm−1; 1H NMR
(CD3OD, 500 MHz) δ 7.99−7.94 (1H, m, H-2), 7.90−7.85 (1H, m,
H-4), 7.60−7.54 (1H, m, H-6), 7.53−7.47 (1H, m, H-7), 7.27−7.24
(1H, s, H-10), 7.23−7.11 (1H, m, H-3), 7.17−7.11 (1H, m, H-5),
3.40−3.34 (2H, m, H2-14), 3.19 (3H, s, H3-17), 2.91−2.82 (2H, m,
H2-13), 2.20 (3H, m, H3-16); 13C NMR (CD3OD, 125 MHz) δ 174.5
(C-15), 151.3 (C-3a), 143.5 (C-2), 142.6 (C-7a), 138.1 (C-11), 136.3
(C-6), 130.3 (C-8a), 127.6 (C-11a), 126.2 (C-4), 124.0 (C-5), 122.7
(C-10), 121.9 (C-11b), 119.1 (C-7), 116.9 (C-9), 11.5 (C-3b), 105.7
1
(C-3), 48.4 (C-13), 37.9 (C-16), 30.3 (C-12), 21.6 (C-15); H NMR
(DMSO-d6, 400 MHz) δ 13.47 (1H, br s, NH-1), 11.54 (1H, br s,
NH-8), 10.83 (1H, br s, OH-12), 8.24 (1H, d, J = 6.6 Hz, H-2), 8.20
(1H, d, J = 8.6 Hz, H-4), 7.70 (1H, t, J = 8.6 Hz, H-6), 7.63 (1H, d, J =
8.6 Hz, H-7), 7.54 (1H, d, J = 6.6 Hz, H-3), 7.42 (1H, s, H-10), 7.23
(1H, t, J = 8.6 Hz, H-5), 3.47−3.41 (2H, m, H2-14), 3.10 (3H, s, H3-
17), 3.05−2.98 (2H, m, H2-13), 2.10 (3H, s, H3-16); 13C NMR
(DMSO-d6, 100 MHz) δ 171.7 (C-15), 149.3 (C-3a), 143.4 (C-2),
141.0 (C-7a), 136.6 (C-11), 135.1 (C-6), 128.5 (C-8a), 125.9 (C-11a),
125.6 (C-4), 122.5 (C-5), 121.4 (C-10), 120.3 (C-11b), 117.7 (C-7),
115.7 (C-9), 113.9 (C-3b), 105.0 (C-3), 46.5 (C-14), 37.0 (C-17),
28.6 (C-13), 21.5 (C-16); (+)-HRESIMS m/z 334.1562 [M + H]+
(calcd for C20H20N3O2, 334.1550).
N-Ethyl-styelsamine B (20). Using general procedure C, kynur-
amine dihydrobromide (7, 0.16 g, 0.50 mmol), N-(3,4-dihydrox-
yphenethyl)-N-ethylacetamide (17, 0.11 g, 0.48 mmol), CeCl3·7H2O
(0.027 g, 0.072 mmol), and Ag2O (0.24 g, 1.10 mmol) afforded 20 as a
purple oil (TFA salt, 27.2 mg, 12% yield).
N-Benzyl-styelsamine D (24). Using general procedure D, N-
benzyl-styelsamine B (21, 20.4 mg, 0.04 mmol) and 6 N HCl (8 mL)
afforded 24 as a purple oil (bis-TFA salt, 9.44 mg, 41% [71% based
upon recovered starting material]). Rt = 8.52 min; IR (ATR) νmax
Rt = 8.98 min; IR (ATR) νmax 3140, 2980, 1586, 1506, 1426, 1194
cm−1; 1H NMR (CD3OD, 500 MHz) δ 7.92 (1H, d, J = 6.7 Hz, H-2),
7.82 (1H, d, J = 8.3 Hz, H-4), 7.54 (1H, dt, J = 7.4, 1.2 Hz, H-6), 7.45
(1H, d, J = 7.4 Hz, H-7), 7.21 (1H, s, H-10), 7.15−7.11 (2H, m, H-3,
5), 3.52 (2H, q, J = 7.1 Hz, H2-16), 3.29 (2H, obscured, H2-13), 2.79
(2H, t, J = 7.0 Hz, H2-12), 2.23 (3H, s, H3-15), 1.28 (3H, t, J = 7.1 Hz,
H3-17); 13C NMR (CD3OD, 125 MHz) δ 173.9 (C-14), 150.8 (C-3a),
1
3402, 2949, 1679, 1584, 1250, 1141, 1030 cm−1; H NMR (CD3OD,
500 MHz) δ 8.12 (1H, d, J = 6.5 Hz, H-2), 8.00 (1H, d, J = 8.2 Hz, H-
4), 7.87 (1H, d, J = 8.0 Hz, H-7), 7.61 (1H, t, J = 8.0 Hz, H-6), 7.59−
F
DOI: 10.1021/acs.joc.5b02312
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The Journal of Organic Chemistry
Note
7.57 (2H, m, H-16, 20), 7.46−7.43 (3H, m, H-17, 18, 19), 7.41 (1H, d,
J = 6.5 Hz, H-3), 7.39 (1H, s, H-10), 7.20 (1H, t, J = 8.2 Hz, H-5),
4.28 (2H, s, H2-14), 3.36−3.34 (2H, m, H2-12), 3.34−3.32 (2H, m,
H2-13); 13C NMR (CD3OD, 125 MHz) δ 151.2 (C-3a), 143.7 (C-2),
142.5 (C-7a), 138.5 (C-11), 136.3 (C-6), 132.5 (C-15), 131.1 (C-16,
20), 130.7 (C-18), 130.3 (C-17, 19), 129.9 (C-8a), 128.3 (C-11a),
126.1 (C-4), 124.2 (C-5), 122.7 (C-10), 121.9 (C-11b), 119.1 (C-7),
115.5 (C-3b), 114.5 (C-9), 106.3 (C-3), 52.5 (C-14), 47.2 (C-13),
28.8 (C-12); (+)-HRESIMS m/z 368.1754 [M + H]+ (calcd for
C24H22N3O, 368.1757).
(2H, s, H2-14); (+)-HRESIMS m/z 412.1055 [M + Na]+ (calcd for
C25H15N3NaO2, 412.1056).
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02312.
1H and 13C NMR spectra for 1, 3−5, and 13−27 and 1H
spectra of 11 and 28 (PDF)
N-Ethyl-demethyldeoxyamphimedine (25). Using general proce-
dure E, N-ethyl-styelsamine D (23, 11.5 mg, 0.02 mmol),
paraformaldehyde (4.1 mg, 0.14 mmol), and acetic acid (2 mL)
afforded 25 as a dark yellow powder (TFA salt, 7.61 mg, 83% yield). Rt
= 8.28 min; IR (ATR) νmax 3401, 1671, 1427, 1183, 1110, 1032 cm−1;
1H NMR (CD3OD, 500 MHz) δ 9.95 (1H, s, H-9), 9.46 (1H, d, J =
5.5 Hz, H-12), 9.39 (1H, d, J = 5.5 Hz, H-11), 9.31 (1H, d, J = 4.9 Hz,
H-6), 9.10 (1H, d, J = 4.9 Hz, H-5), 8.94 (1H, d, J = 8.0 Hz, H-4), 8.49
(1H, d, J = 8.0 Hz, H-1), 8.12 (1H, t, J = 8.0 Hz, H-2), 8.04 (1H, t, J =
8.0 Hz, H-3), 4.94 (2H, q, J = 7.2 Hz, H2-14), 1.82 (3H, t, J = 7.2 Hz,
H3-15); 13C NMR (CD3OD, 125 MHz) δ 179.2 (C-8), 151.4 (C-6),
149.7 (C-12a), 148.2 (C-11), 147.2 (C-7a), 146.8 (C-9), 146.7 (C-
13a), 145.5 (C-12b), 139.8 (C-4b), 134.0 (C-2), 133.3 (C-1), 133.0
(C-3), 132.0 (C-8a), 125.2 (C-4), 125.0 (C-12), 124.2 (C-4a), 122.9
(C-5), 120.9 (C-12c), 59.1 (C-14), 16.8 (C-15); (+)-HRESIMS m/z
312.1125 [M]+ (calcd for C20H14N3O, 312.1131).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: b.copp@auckland.ac.nz.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of Auckland for funding this project.
REFERENCES
■
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1
9.07 min; IR (ATR) νmax 3408, 1691, 1636, 1250, 1129 cm−1; H
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NMR (CD3OD, 500 MHz) δ 10.02 (1H, s, H-9), 9.49 (1H, d, J = 6.5
Hz, H-12), 9.38 (1H, d, J = 6.5 Hz, H-11), 9.36 (1H, d, J = 5.3 Hz, H-
6), 9.16 (1H, d, J = 5.3 Hz, H-5), 9.00 (1H, d, J = 8.0 Hz, H-4), 8.53
(1H, d, J = 8.0 Hz, H-1), 8.14 (1H, t, J = 8.0 Hz, H-2), 8.08 (1H, t, J =
8.0 Hz, H-3), 7.69−7.63 (2H, m, H-16, 20), 7.56−7.51 (3H, 17, 18,
19), 6.09 (2H, s, H2-14); 13C NMR (CD3OD, 125 MHz) δ 179.2 (C-
8), 151.4 (C-6), 150.2 (C-12a), 148.2 (C-11), 147.3 (C-7a)a, 146.8
(C-9, 13a), 145.6 (C-12b)a, 139.9 (C-4b), 134.3 (C-15), 134.0 (C-2),
133.3 (C-1), 133.0 (C-3), 132.4 (C-8a), 131.3 (C-18), 130.9 (C-17,
19), 130.5 (C-16, 20), 125.3 (C-4, 12), 124.4 (C-4a), 122.9 (C-5),
121.1 (C-12c), 66.1 (C-14); (+)-HRESIMS m/z 374.1275 [M] (calcd
for C25H16N3O, 374.1288).
N-Ethyl-demethylamphimedine (27). Using general procedure F,
N-ethyl-demethyldeoxyamphimedine (25, 4.61 mg, 0.011 mmol),
NaOH (1.73 mg, 0.043 mmol, in 0.3 mL of water), and potassium
ferricyanide (7.14 mg, 0.022 mmol, in 0.3 mL of water) afforded 27 as
a yellow powder (3.01 mg, 85%). Rf (CH2Cl2/MeOH, 9:1) 0.18; IR
(ATR) νmax 3408, 2924, 1738, 1638, 1217, 1090 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 9.29 (1H, br s, H-6), 8.79 (1H, s, H-9), 8.67−
8.57 (2H, m, H-4, 5), 8.35 (1H, d, J = 7.8 Hz, H-1), 8.01 (1H, s, H-
12), 7.98 (1H, t, J = 7.8 Hz, H-2), 7.86 (1H, t, J = 7.8 Hz, H-3), 4.24
(2H, q, J = 7.4 Hz, H2-14), 1.54 (3H, t, J = 7.4 Hz, H3-15); 13C NMR
(CDCl3, 125 MHz) δ 179.1 (C-8), 162.5 (C-11), 150.0 (C-6), 147.7
(C-7a), 146.7 (C-12b), 145.4 (C-13a), 144.0 (C-9), 142.9 (C-12a),
138.4 (C-4b), 132.1 (C-2), 131.9 (C-1), 129.6 (C-3), 123.0 (C-4),
122.3 (C-4a), 119.9 (C-12c), 119.4 (C-5), 114.6 (C-12), 113.8 (C-8a),
46.2 (C-14), 14.9 (C-15); (+)-HRESIMS m/z 350.0890 [M + Na]+
(calcd for C20H13N3NaO2, 350.0900).
́
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G
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H
DOI: 10.1021/acs.joc.5b02312
J. Org. Chem. XXXX, XXX, XXX−XXX