Total Synthesis of Phenanthroindolizidine Alkaloids by Combining Iodoaminocyclization with Free Radical Cyclization

Article abstract of DOI:10.1021/acs.joc.6b01161

A concise and modular synthesis of phenanthroindolizidine alkaloids was achieved by combining iodoaminocylization with a free radical cyclization approach. The route described allowed the preparation of (±)-tylophorine, (±)-antofine, and (±)-deoxypergularinine in six steps. When commercially available l-prolinol was used as a chiral building block, (S)-(+)-tylophorine was also synthesized in 49% yield and >99% ee over five linear steps.

Full text of DOI:10.1021/acs.joc.6b01161

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Note
Total Synthesis of Phenanthroindolizidine Alkaloids by
Combining Iodoaminocyclization with a Free Radical Cyclization
Gong-Qing Liu, Marcel Reimann, and Till Opatz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01161 • Publication Date (Web): 17 Jun 2016
Downloaded from http://pubs.acs.org on June 20, 2016
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Total Synthesis of Phenanthroindolizidine
Alkaloids by Combining Iodoaminocyclization
with a Free Radical Cyclization
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GongꢀQing Liu, Marcel Reimann, and Till Opatz *
Institute of Organic Chemistry, Johannes Gutenberg University, Duesbergweg 10–14,
5
5128 Mainz, Germany
Abstract Graphics
Abstract
A concise and modular synthesis of phenanthroindolizidine alkaloids was achieved by
combining iodoaminocylization with a free radical cyclization approach. The route
described allowed the preparation of (±)ꢀtylophorine, (±)ꢀantofine as well as
(±)ꢀdeoxypergularinine in six steps. Using commercially available Lꢀprolinol as a
chiral building block, (S)ꢀ(+)ꢀtylophorine was also synthesized in 49% yield and
>99% ee over five linear steps.
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The phenanthroindolizidine alkaloids represent a group of pentacyclic natural
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products (Figure. 1) which exhibit various biological activities such as antiꢀtumor,
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3
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antiꢀarthritis, antiꢀinflammatory and antiꢀlupus effects. To date, close to 100
structurally related phenanthroindolizidines together with their secoꢀderivatives and
Nꢀoxides have been isolated, characterized from the genera Cynanchum, Pergularia,
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and Tylophora. Due to their potent biological activities, they represent interesting
targets for synthesis, structural modification, and structureꢀactivity relationship (SAR)
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studies since their first isolation in 1935.
Figure 1. Representative of phenanthroindolizidine alkaloids.
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Since the first total synthesis of (±)ꢀtylophorine in 1961, continuous efforts have
been devoted to the total synthesis of phenanthroindolizidine alkaloids owing to their
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potent biological activity and their partly low natural abundance. These strategies
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include intramolecular double Michael reactions, Friedel–Crafts acylation,
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intramolecular cycloadditon, as well as biomimetic syntheses.
With respect to enantioselective approaches, several enantioselective synthetic
8b
strategies have been reported in the literature so far. One representative strategy,
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first reported by Rapoport and Buckley, used the exꢀchiralꢀpoolꢀapproach which was
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also employed in later syntheses based on proline,
aminoadipate,
and
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pyroglutamate. Other strategies included a chiral auxiliary approach, the use of a
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chiral allylic alcohol, enantioselective carboamination, and enantioselective
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phaseꢀtransfer alkylation.
Nevertheless, low enantiomeric purity of the product is an issue in many of the
reported syntheses and there is still a need for highꢀyielding, straightforward and
generally applicable approaches to these natural products. Since the enantiomeric
series of the phenanthroꢀalkaloids possess different bioactivity profiles, syntheses
providing products of high optical purity are of particular value. Herein, we report a
general, practical and fully modular access to phenanthroindolizidine alkaloids
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through an iodoaminocyclization of unactivated olefins and free radical ring closure
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process.
A retrosynthetic analysis for tylophorine is shown in Scheme 1. The target molecule
1
a could be accessible via reduction of amide 2 which was envisioned to be
constructed from compound 4 through an iodoaminocyclization followed by a free
radical ring closure. Compound 4 could be easily prepared from commercially
available veratric aldehyde and homoveratric acid by the Perkin reaction, followed by
amide coupling and intramolecular oxidative coupling.
Scheme 1. Retrosynthetic analysis of tylophorine.
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The synthesis began with preparation of 2,3ꢀdiphenylacrylic acid 6 by condensation of
veratraldehyde and homoveratric acid in a mixture of triethylamine and acetic
anhydride. This compound underwent oxidative cyclization upon treatment with
sodium nitrite and air in acid medium to furnish the phenanthreneꢀ9ꢀcarboxylic acid
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5
.
EDCꢀcoupling of 5 with pentꢀ4ꢀenꢀ1ꢀamine gave the aminoiodocyclization
precursor 4 in 90% isolated yield (Scheme 2).
Scheme 2. Synthesis of olefinic amide 4.
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OMe
COOH
MeO
CHO
OMe
Ac O/Et N
20% NaNO , air
2
o
3
2
CH CN/TFA (4:1), r.t.
100 C, 24 h
8%
3
8
94%
MeO
MeO
MeO
COOH
OMe
OMe
MeO
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OMe
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OMe
O
MeO
N
NH2
COOH
H
.
EDC HCl, DMAP,
CH Cl , r.t.
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2
MeO
90%
MeO
OMe
OMe
4
5
Initial attempts for the iodoaminocyclization of amide 4 were performed with
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(
diacetoxyiodo)benzene and potassium iodide. Under these reaction conditions,
iodoaminocyclization of 4 did not occur (Table 1, entry 1). PhI(OAc)
2
in combination
with TSMI promoted iodoamidation of 4, but gave the desired product only in low
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yield (entry 2). The substrate was also inert towards Nꢀiodosuccinimide (NIS) (entry
3
). However, formation of the desired compound 3 from olefinic amide 4 could be
accomplished with molecular iodine and sodium hydrogen carbonate in acetonitrile in
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moderate yield (entry 4). Prolonged reaction time and elevated reaction temperature
significantly increased the yield of iodoamidation product 3 (entry 5). There are
surprisingly few literature reports on iodoaminocyclizations of this type and they
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mostly utilize amides preactivated by Oꢀsilylation or alkylation. In addition, no
iodination of the electron rich phenanthrene core took place in our case.
a
Table 1. Optimization studies for iodoaminocyclization.
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entry
reagent
PhI(OAc) , KI
temp.
r.t.
isolated yield (%)
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<1
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<1
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PhI(OAc) , TMSI
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I
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, NaHCO
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, NaHCO
90 °C
a
2 2
Reaction conditions: substrate (0.5 mmol), reagent (0.55 mmol), CH Cl (10 mL), 24
b
c
3
h. reagent (0.3 mmol), CH CN as solvent. 36 h.
With radical precursor 3 in hand, we turned to our attention to radical ring closure to
construct the Dꢀring of tylophorine. Recently, Alexanian reported the
palladiumꢀcatalyzed direct ringꢀforming C–H alkylation for the construction of
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indoline derivatives via a free radical process using simple alkyl halides. We
envisioned that cyclization of the iodide 3 using the aboveꢀmentioned method would
be perfectly suited to construct the Dꢀring of tylophorine. We were delighted to find
that cyclization of the iodide 3 proceeded readily using 10 mol% Pd(PPh
3 4
) as the
catalyst, giving the desired pentacyclic lactam 2 in 83% yield (Scheme 3). Finally,
reduction of lactam 2 with LiAlH
4
completed the synthesis of (±)ꢀtylophorine 1a,
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which was obtained in 41% overall yield over six steps.
Scheme 3. Synthesis of (±)ꢀtylophorine.
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In previous work in the phenanthroquinolizidine series, we have successfully
employed a Zardꢀtype radical cyclization of a xanthate to close the Dꢀring at the same
oxidation state. The preparation of the radical precursor was however more lengthy
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than the present route. To investigate whether the stereochemical integrity of the
neighboring αꢀcenter is retained during radical generation and cyclization, we
performed a synthesis of (S)ꢀtylophorine using the same ring closure on a precursor
synthesized from commercial
Lꢀprolinol. Thus, phenanthreneꢀ9ꢀcarboxylic acid 5 and
Lꢀprolinol were coupled with EDC, followed by subsequent conversion to iodide (S)-3
in a oneꢀpot procedure. Iodide (S)-3 was subjected to the Pdꢀcatalyzed radical
cyclization resulting in the pentacyclic lactam (S)-2 in 85% yield. Reduction with
4
LiAlH produced (S)ꢀ(+)ꢀtylophorine (S)-1a with excellent enantiomeric excess (>99%
ee) and in high yield (Scheme 4).
Scheme 4. Synthesis of (S)ꢀtylophorine.
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This approach allows for a variation at the oxygenꢀsubstituted aromatic rings A and C,
so the strategy was also applied to the synthesis of antofine. The phenanthrene
carboxylate 7 was prepared by condensation of 2ꢀ(4ꢀmethoxyphenyl)acetic acid and
veratraldehyde, followed by sodium nitrite mediated ring closure. The olefinic amide
8
was readily obtained in 89% yield by EDCꢀcoupling of 7 with pentꢀ4ꢀenꢀ1ꢀamine
(Scheme 5). Iodocylization produced lactam 9 in acceptable isolated yield. To our
surprise, two products in almost equimolar ratio were obtained simultaneously when a
radical cyclization of 9 to 10 based on Alexanian’s method was carried out in
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,4ꢀdioxane. 10a and 10b could be separated by flash column chromatography and
structure of the compounds were also established by 2D NMR experiments, which
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were in agreement with results reported by Su and coꢀworkers. In a last step,
antofine (1b) and deoxypergularinine (1c) were obtained from 10a and 10b through
4
reduction with LiAlH in high yield.
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Scheme 5. Synthesis of (±)ꢀantofine and (±)ꢀdeoxypergularinine.
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The formation of the regioisomers 10a and 10b can be rationalized on the basis of the
mechanism shown in Scheme 6. The reaction is initiated by a reversible single
electron oxidative addition of the iodide 9 and generates the carbonꢀcentered radical
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A, which can either add in a 1,6ꢀfashion to give lactam 10a after rearomatization of
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the radical intermediate B, or by 1,5ꢀaddition (ipso attack), giving rise to spirocyclic
intermediate C. Intermediate C can then undergo radical migration through path a to
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B or path b to D. Rearomatization of radical B and D could occur via singleꢀelectron
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oxidation followed by deprotonation to give the lactam 10a and 10b, respectively.
Scheme 6. Plausible mechanism for radical cyclization.
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The observed formation of equal amounts of the two regioisomeric products 10a and
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0b suggests that the 1,5ꢀaddition is the dominant cyclization process. A similar
observation of two regioisomers being formed in equimolar ratio had already been
made by Alexanian and coworkers although the possibility of a 1,5ꢀcyclization was
not taken into consideration in favor of a 1,6ꢀcyclization followed by a 1,2ꢀalkyl shift
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which is not an option in our case.
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In summary, a strategy for the synthesis of phenanthroindolizidine alkaloids is
presented comprising a iodoaminocylization and a radical ring closure process as the
key steps furnishing this class of alkaloids in six steps from readily available starting
materials. Using the same cyclization step, the highly stereoselective synthesis of
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(
S)ꢀtylophorine was achieved using readily available Lꢀprolinol from the chiral pool. It
requires only five steps, provides the target compound in an overall yield of 49% with
an enantiomeric excess of more than 99%, and is devoid of any protecting group
manipulations. To the best of our knowledge, this represents the shortest asymmetric
synthesis of tylophorine known so far.
Experimental Section
General experimental information: All reactions requiring the exclusion of air
and/or moisture were conducted in flameꢀdried glassware under an argon atmosphere.
Solvents were dried and distilled prior to use. THF was distilled from
2 2
potassium/benzophenone under an argon atmosphere. CH Cl was dried over calcium
hydride and distilled under an argon atmosphere. Ethyl acetate and cyclohexane were
purchased in technical quality and were purified by distillation. All other chemicals
were purchased from commercial suppliers and used without prior purification unless
otherwise stated. Flash chromatography was performed on silica of 25−40 ꢁm particle
size. NMR spectra were recorded on 300, 400 or 600 MHz spectrometers using
standard pulse sequences. Chemical shifts are expressed in ppm relative to
1
tetramethylsilane referenced to the residual solvent signals (CDCl
3
: H, δ = 7.26 ppm;
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C, δ = 77.16 ppm. DMSOꢀd : H, δ = 2.50 ppm; C, δ = 39.52 ppm). ESIꢀHRMS
was performed on a QꢀTOF instrument with a dual source and a suitable external
calibrant. Thinꢀlayer chromatography (TLC) was carried out on 0.25 mm silica gel
plates with a fluorescence indicator. Melting points were measured on an
electrothermal apparatus with a digital thermometer.
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(E)-2,3-Bis(3,4-dimethoxyphenyl)acrylic acid (6). A mixture of homoveratric acid
(1.96 g, 10 mmol), veratraldehyde (1.83 g, 11 mmol), acetic anhydride (10 mL), and
triethylamine (5 mL) was heated to reflux for 24 h with the exclusion of moisture. The
solution was allowed to cool to room temperature, water (200 mL) was added, and the
mixture was stirred for 1 h. The mixture was then poured into aqueous potassium
carbonate (30.0 g in 80 mL water) and refluxed until nearly all the gummy material
was dissolved. The solution obtained was cooled and carefully acidified with
concentrated hydrochloric acid (pH 4~5) to produce a white precipitate. The solid was
collected and recrystallized from methanol to give compound 6 as a white solid (3.03
10b
1
g, 88%). Mp: 215–216 °C (ref, Mp: 214–216 °C). H NMR (300 MHz, DMSO) δ =
12.45 (s, 1H), 7.70 (s, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.84–6.78 (m, 3H), 6.75–6.64 (m,
13
1
H), 6.56 (s, 1H), 3.77 (s, 3H), 3.71 (s, 3H), 3.68 (s, 3H), 3.37 (s, 3H). C NMR (75
MHz, CDCl ) δ = 173.5, 150.7, 149.6, 149.0, 148.5, 142.6, 129.0, 128.5, 127.4, 126.1,
3
1
22.6, 113.2, 112.9, 111.8, 110.8, 56.2, 56.1, 56.0, 55.5. Spectral data are in
10b
agreement with literature values.
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,3,6,7-Tetramethoxyphenanthrene-9-carboxylic acid (5). To a solution of
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4
5
6
7
8
9
compound 6 (344 mg, 1.00 mmol) in TFA/CH
3 2
CN (1:4) (10 mL) was added NaNO
(13.8 mg, 200 ꢁmol) under an atmosphere of air. The mixture was stirred at room
temperature for 1 h, and water (10 mL) was added to the mixture, and then filtered
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
and washed with EtOAc to give compound 5 as a white solid (321.6 mg, 94%). Mp:
23
34
1
2
85–286 °C (ref, Mp: 283–285 °C; ref, Mp: 285–286 °C). H NMR (300 MHz,
DMSO) δ = 12.88 (brs, 1H), 8.56 (s, 1H), 8.43 (s, 1H), 8.06 (s, 1H), 8.02 (s, 1H), 7.57
1
3
(
s, 1H), 4.07 (s, 3H), 4.06 (s, 3H), 3.92 (s, 3H), 3.90 (s, 3H). C NMR (75 MHz,
DMSO) δ =169.5, 151.5, 149.3, 149.2, 130.2, 126.9, 125.3, 124.6, 123.9, 123.0, 109.9,
1
07.1, 104.2, 103.8, 56.4, 56.2, 56.0, 55.6. Spectral data are in agreement with
23
literature values.
2,3,6,7-Tetramethoxy-N-(pent-4-en-1-yl)phenanthrene-9-carboxamide (4). At
0
°C, acid
5
(342 mg, 1.00 mmol) was added to a solution of
.
1ꢀethylꢀ3ꢀ(3ꢀdimethylaminopropyl)carbodiimide hydrochloride (EDC HCl) (211 mg,
1
.10 mmol) and DMAP (12.2 mg, 1.00 mmol) in CH Cl (25 mL). Then,
2 2
2
4
pentꢀ4ꢀenꢀ1ꢀamine (85.1 mg, 1.00 mmol) was added to the mixture. The ice bath
was removed and warmed to room temperature. After 24 h at room temperature, the
solution was diluted with Et
aqueous layer was then extracted twice with Et
were dried with Na SO and concentrated to give crude amide, which was purified by
2
O (20 mL) and washed with 1N HCl solution. The
2
O (20 mL). The combined ether layers
2
4
flash column chromatography (cyclohexane/EtOAc = 2/1) to give compound 4 as a
1
white solid (368.3 mg, 90%). Mp: 175–176 °C. H NMR, COSY (300 MHz, CDCl
3
) δ
=
7.72 (s, 1H, PhenꢀH10), 7.57 (s, 1H, PhenꢀH4), 7.52 (s, 1H, PhenꢀH5), 7.51 (s, 1H,
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2
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5
5
6
PhenꢀH1), 7.01 (s, 1H, PhenꢀH9), 6.52 (t, J = 5.5 Hz, 1H, ꢀNHꢀ), 5.89 (ddt, J = 16.9,
3
1
4
1
0.2, 6.6 Hz, 1H, ꢀCH=CH
2
), 5.17–4.98 (m, 2H, ꢀCH=CH
2
), 4.07 (s, 3H, C ꢀOCH
3
),
6
2
7
.05 (s, 3H, C ꢀOCH
3
), 3.98 (s, 3H, C ꢀOCH
3
), 3.96 (s, 3H, C ꢀOCH
3
), 3.55 (dd, 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
3.2, 6.9 Hz, 2H, ꢀNHCH ꢀ), 2.29–2.18 (m, 2H, ꢀCH CH=CH ), 1.87–1.75 (m, 2H,
2
2
2
13
ꢀCH
2
CH
2
CH
2
ꢀ). C NMR, HSQC, HMBC (75 MHz, CDCl
3
) δ = 170.3 (CONH),
3
6
2,7
1
1
1
2
49.5 (C ꢀOMe), 148.7 (C ꢀOMe), 148.4 (C ꢀOMe), 137.7 (ꢀCH=CH ), 130.1 (C9),
2
24.9 (C10), 124.5 (C10a), 124.4 (C4b), 123.5 (C4a), 122.7 (C8a), 115.3 (ꢀCH=CH ),
2,3,6,7
08.2 (C8), 105.9 (C1), 102.2 (C4), 102.0 (C5), 55.7 (C
ꢀOMe), 39.4 (C1'), 31.2
+
(
C3'), 28.9 (C2'). HRMS–ESI (m/z): [M+H] calcd for C H NO , 410.1967; found:
24 27
5
4
10.1976.
(2-(Iodomethyl)pyrrolidin-1-yl)(2,3,6,7-tetramethoxyphenanthren-9-yl)methanon
e (3). To a stirred solution of amide 4 (204 mg, 500 ꢁmol) in CH CN (10 mL)
containing solid NaHCO (126 mg, 1.50 mmol) was added I (381 mg, 1.50 mmol) in
portions. The reaction mixture was stirred for 36 h at 90 °C. The reaction mixture was
allowed to cool to ambient temperature. CH Cl (10 mL) was then added, and the
mixture was washed with aqueous Na . The combined organic layer was dried
with Na SO and concentrated to give crude residue, which was purified by flash
3
3
2
2
2
2 2 3
S O
2
4
column chromatography (cyclohexane/EtOAc = 1/1) to give the compound 3 as
1
yellow oil (192.7 mg, 72%). H NMR, COSY (400 MHz, CDCl ) δ = 7.80 (s, 1H,
3
PhenꢀH10), 7.77 (s, 1H, PhenꢀH4), 7.60 (s, 1H, PhenꢀH5), 7.38 (s, 1H, PhenꢀH1),
3
7.20 (s, 1H, PhenꢀH9), 4.36–4.31 (m, 1H, ꢀCH
2
I), 4.14 (s, 3H, C ꢀOCH
3
), 4.13 (s, 3H,
6
2
C ꢀOCH
3
), 4.10–4.08 (m, 1H, Hꢀ2'), 4.03 (s, 3H, 3H, C ꢀOCH
3
), 4.03 (s, 3H, 3H,
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C ꢀOCH
3
), 3.69 (dd, J = 9.7, 2.3 Hz, 1H, ꢀCH
2
I), 3.44–3.37 (m, 1H, Hꢀ5'), 3.29–3.24
(
m, 1H, Hꢀ5'), 2.33–2.19 (m, 1H, Hꢀ3'), 2.02–1.89 (m, 2H, Hꢀ3' and Hꢀ4'), 1.82–1.70
1
3
(
3
m, 1H, Hꢀ4'). C NMR, HSQC, HMBC (100 MHz, CDCl ) δ = 170.4 (CO), 150.0
10
11
12
13
14
15
16
17
18
19
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21
22
23
24
25
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48
49
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56
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3
6
2
7
(
C ꢀOMe), 149.4 (C ꢀOMe), 149.2 (C ꢀOMe), 149.1 (C ꢀOMe), 131.3 (C9), 125.2
(
C10), 124.9 (C10a), 124.8 (C4b), 123.1 (C4a), 122.3 (C8a), 108.5 (C8), 105.7 (C1),
3
6
3,7
1
03.0 (C4), 102.7 (C5), 57.1 (C ꢀOCH
3
), 56.4 (C ꢀOCH
3
), 56.1 (C ꢀOCH
3
), 56.0
+
(
C1'), 50.3 (C5'), 31.6 (C2'), 24.6 (C4'), 12.5 (ꢀCH
calcd for C24 , 536.0934; found: 536.0925.
,3,6,7-Tetramethoxy-12,13,13a,14-tetrahydrodibenzo[f,h]pyrrolo[1,2-b]isoquinol
in-9(11H)-one (2). A vial in a glove box under argon atmosphere was charged with
iodide 3 (53.5 mg, 100 ꢁmol) and 1,4ꢀdioxane (1 mL). Pd(PPh (11.6 mg, 10 ꢁmol)
and K PO (42.4 mg, 200 ꢁmol) were subsequently added. The reaction vial was
2
I). HRMS–ESI (m/z): [M+H]
H
26INO
5
2
3 4
)
3
4
removed from the glove box and heated in oil bath at 100 °C, stirring for 24 h. The
reaction mixture was allowed to cool to ambient temperature, was quenched with 1N
HCl and the aqueous layer was extracted with CH
was dried with Na SO and concentrated to give crude residue, which was purified by
flash column chromatography (cyclohexane/EtOAc = 1/2) to give lactam 2 as white
2 2
Cl . The combined organic layer
2
4
35
36
solid (33.9 mg, 83%). Mp: 282–283 °C (ref, Mp: 283–289; ref, Mp: 284–286 °C).
1
H NMR, COSY (400 MHz, CDCl ) δ = 9.03 (s, 1H, PhenꢀH4), 7.74 (s, 1H, PhenꢀH5),
3
3
7
.72 (s, 1H, PhenꢀH8), 7.22 (s, 1H, PhenꢀH1), 4.13 (s, 3H, C ꢀOCH
3
), 4.11 (s, 3H,
6
2
7
3 3 3
C ꢀOCH ), 4.09 (s, 3H, C ꢀOCH ), 4.02 (s, 3H, C ꢀOCH ), 3.91–3.76 (m, 3H, Hꢀ11,
Hꢀ13), 3.50 (dd, J = 15.6, 4.1 Hz, 1H, Hꢀ14), 2.86 (dd, J = 15.6, 13.4 Hz, 1H, Hꢀ14),
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
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5
5
5
5
5
5
5
5
6
2
.44–2.37 (m, 1H, Hꢀ13a), 2.20–2.14 (m, 1H, Hꢀ12), 1.99–1.87 (m, 2H, Hꢀ12, Hꢀ13).
1
3
3
C NMR, HSQC, HMBC (100 MHz, CDCl
3
) δ =164.7 (CO), 150.2 (C ꢀOMe), 148.9
C ꢀOMe), 148.7 (C ꢀOMe), 148.6 (C ꢀOMe), 133.2(C14), 126.6 (C8a), 124.3 (C14a),
24.3 (C8b), 123.1 (C4a), 122.4 (C4b), 108.0 (C1), 104.8 (C8), 103.0 (C4), 102.3
6
2
7
(
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
1
3
,6,2
7
(C5), 56.0 (C ꢀOCH
3 3
), 55.9 (C13a), 55.2 (C ꢀOCH ), 45.4 (C11), 33.9 (C14), 32.5
35
(C12), 23.5 (C13). Spectral data are in agreement with literature values.
rac-Tylophorine (1a). Under a nitrogen atmosphere, to a stirred suspension of
LiAlH (17.0 mg, 500 ꢁmol) in dry THF (50 mL) was added the solution of lactam 2
40.7 mg, 100 ꢁmol) in THF (50 mL) dropwise at 0 °C, and the mixture was stirred
4
(
overnight. The resulting suspension was cooled to 0 °C and quenched by slow
addition of 6 M NaOH (10 mL). The resulting mixture was extracted with ether (4 x
3
0 mL) and the combined ether extracts were dried with Na
give crude residue which was purified by flash column chromatography
EtOAc/MeOH = 1/10) to give racꢀtylophorine 1a as a pale yellow solid (36.2 mg,
2 4
SO and concentrated to
(
37
10b
1
92%). Mp: 279–280 °C (ref, Mp: 279–281 °C; ref, Mp: 275–282 °C). H NMR,
COSY (400 MHz, CDCl
3
) δ = 7.73 (s, 1H, PhenꢀH4), 7.72 (s, 1H, PhenꢀH5), 7.18 (s,
2
1H, , PhenꢀH8), 7.06 (s, 1H, PhenꢀH1), 4.52 (d, J = 14.7 Hz, 1H, Hꢀ9), 4.02 (s, 6H,
3,6
2
7
2
C ꢀOCH
Hꢀ9), 3.38 (td, J = 8.5, 2.0 Hz, 1H, Hꢀ11), 3.27 (dd, J = 15.8, 2.4 Hz, 1H, Hꢀ14), 2.81
dd, J = 15.8, 10.5 Hz, 1H, Hꢀ14), 2.44–2.31 (m, 2H, Hꢀ13a, Hꢀ11), 2.17–2.12 (m, 1H,
Hꢀ12), 2.02–1.89 (m, 1H, Hꢀ13 ), 1.88–1.77 (m, 1H, Hꢀ13), 1.74–1.61 (m, 1H, Hꢀ12).
3 3 3
), 4.00(s, 3H, C ꢀOCH ), 4.00 (s, 3H, C ꢀOCH ), 3.56 (d, J = 14.7 Hz, 1H,
(
13
3,6
2,7
3
C NMR, HMBC, HSQC (100 MHz, CDCl ) δ =148.6 (C ꢀOMe), 148.4 (C ꢀOMe),
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26.3 (C14) , 126.0 (C8a), 125.8 (C14a), 124.3 (C8b), 123.6 (C4a), 123.6 (C4b),
3
,6
1
03.9 (C1), 103.4 (C8), 103.2 (C4), 103.1 (C5), 60.2 (C13a), 56.0 (C ꢀOCH
3
), 55.9
2
,7
(
C ꢀOCH
are in agreement with literature values.
S)-(2-(Iodomethyl)pyrrolidin-1-yl)(2,3,6,7-tetramethoxyphenanthren-9-yl)metha
3
), 55.2 (C11), 54.1 (C9), 33.9 (C14), 31.3 (C12), 21.6 (C13). Spectral data
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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44
45
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48
49
50
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53
54
55
56
57
58
59
60
37
(
none ((S)-3). At 0 °C, acid 5 (342 mg, 1.00 mmol) was added to a solution of
.
EDC HCl (211 mg, 1.10 mmol) and DMAP (12.2 mg, 100 ꢁmol) in CH
2
2
Cl (25 mL).
Then,
Lꢀprolinol (101 mg, 1.00 mmol) was added to the mixture. The ice bath was
removed and warmed to room temperature and the reaction mixture was stirred 24 h
at room temperature. Then, triphenylphosphine (288 mg, 1.10 mmol), imidazole (74.8
mg, 1.10 mmol), and iodine (279 mg, 1.10 mmol) were added to reaction mixture.
After 3 h the reaction mixture was quenched with saturated aqueous sodium hydrogen
carbonate solution (50 mL) and the organic layer was washed with saturated aqueous
sodium thiosulfate solution (100 mL) and 1N HCl solution, dried with Na SO and
2
4
concentrated to give crude amide, which was purified by flash column
chromatography (cyclohexane/EtOAc = 1/1) to give compound (S)-3 as a yellow oil
D
(395.9 mg, 74%). [α]22= –9.2 (c = 0.5, CHCl
3
). The NMR data correspond to those of
the racemic compound.
(S)-2,3,6,7-Tetramethoxy-12,13,13a,14-tetrahydrodibenzo[f,h]pyrrolo[1,2-b]isoqu
inolin-9(11H)-one ((S)-2). Compound (S)-2 was synthesized from compound (S)-3
(53.5 mg) via the same procedure employed to synthesize compound 2. Compound
(S)-2 was purified by flash column chromatography (cyclohexane/EtOAc = 1/2) as a
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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
3
8
22b
yellow solid (34.6 mg, 85%). Mp: 288–289 °C (ref, Mp: 287–289 °C; ref, Mp:
D
39
D
2
86–287 °C). [α]22= +157.9 (c = 1.0, CHCl
3
) (ref, [α]25 = +165.4, c=1.04, CHCl
3
).
The NMR data correspond to those of the racemic compound.
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
(
(
(
S)-Tylophorine ((S)-1a). Compound (S)-1a was synthesized from compound (S)-2
40.7 mg) via the same procedure employed to synthesize compound 1a. Compound
S)-1a was purified by flash column chromatography (EtOAc/MeOH = 1/10) to yield
22c
a yellow solid (36.2 mg, 92%). Mp: 282–283 °C (ref, Mp: 280–283 °C). Chiral
®
HPLC analysis (CHIRALPAK
ADꢀH, 20% 2ꢀpropanol/nꢀhexane→35%
ꢀ1
2
ꢀpropanol/nꢀhexane in 15 min, 40 °C, 1.0 mL min , 10.34 min (S isomer), 12.18 min
(
R isomer)) showed that the compound (S)-1a had an enantiomeric excess of > 99%.
D
22c
D
39
D
[α]22= +79.0 (c = 0.5, CHCl
0.57, CHCl ). The NMR data correspond to those of the racemic compound.
2,3,6-Trimethoxyphenanthrene-9-carboxylic acid (7). Compound
synthesized from (E)ꢀ3ꢀ(3,4ꢀdimethoxyphenyl)ꢀ2ꢀ(4ꢀmethoxyphenyl)acrylic acid
(314.1 mg) via the same procedure (NaNO 13.8 mg) employed to synthesize
3 3
) (ref, [α]22= +78.9, c = 0.5, CHCl ; ref, [α]22= +64.2, c
=
3
7
was
2
compound 4. Compound 7 was purified by flash column chromatography
(cyclohexane/EtOAc = 2/1) as a yellow solid (287.1 mg, 92%). Mp: 221–222 °C (ref,
22e
40
1
Mp: 222 °C; ref, Mp: 232ꢀ233 °C). H NMR, COSY (400 MHz, CDCl
(brs, 1H, COOH), 9.06 (d, J = 9.3 Hz, 1H, PhenꢀH8), 8.47 (s, 1H, PhenꢀH10), 8.16 (s,
H, PhenꢀH4), 8.14 (d, J = 2.6 Hz, 1H, PhenꢀH5), 7.56 (s, 1H, PhenꢀH1), 7.29 (dd, J
3
) δ =11.20
1
3
2
3 3
= 9.3, 2.6 Hz, 1H, PhenꢀH7), 4.12 (s, 3H, C ꢀOCH ), 4.04 (s, 3H, C ꢀOCH ), 4.03 (s,
6
13
3
H, C ꢀOCH
3
). C NMR, HSQC, HMBC (100 MHz, Acetone) δ=168.3(COOH),
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58.3 (C
q q q
ꢀOMe), 151.7 (C ꢀOMe), 150.3 (C ꢀOMe), 132.0 (C4b), 129.7 (C10), 128.3
(C8), 126.8 (C4a), 125.7 (C10a), 123.4 (C9), 123.3 (C8a), 116.1 (C7), 109.5 (C1),
3
2
6
1
3 3 3
04.1 (C5), 103.7 (C4), 55.5 (C ꢀOCH ), 55.2 (C ꢀOCH ), 54.9 (C ꢀOCH ). Spectral
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
2
2e
data are in agreement with literature values.
2
8
,3,6-Trimethoxy-N-(pent-4-en-1-yl)phenanthrene-9-carboxamide (8). Compound
was synthesized from compound 7 (312.1 mg) via the same procedure employed to
synthesize compound 4. Compound 8 was purified by flash column chromatography
1
(
cyclohexane/EtOAc = 2/1) as a yellow solid (337.5 mg, 89%). Mp: 166–167 °C. H
NMR, COSY (400 MHz, CDCl ) δ = 8.20 (d, J = 9.1 Hz, 1H, PhenꢀH8), 7.70 (d, J =
3
2
.5 Hz, 1H, PhenꢀH5), 7.63 (s, 1H, PhenꢀH4), 7.47 (s, 1H, PhenꢀH4), 7.17 (dd, J = 9.1,
2.5 Hz, 1H, PhenꢀH7), 7.01 (s, 1H, PhenꢀH1), 6.45 (brs, 1H, NH), 5.89 (ddt, J = 16.9,
3
1
0.2, 6.6 Hz, 1H, ꢀCH=CH
2
), 5.17–4.99 (m, 2H, ꢀCH=CH
2
), 4.04 (s, 3H, C ꢀOCH
3
),
2
6
3.99 (s, 3H, C ꢀOCH
3
), 3.97 (s, 3H, C ꢀOCH
3
), 3.54 (dd, J = 13.2, 6.9 Hz, 2H,
13
ꢀ
NHCH ꢀ), 2.26–2.18 (m, 2H, ꢀCH CH=CH ), 1.85–1.75 (m, 2H, ꢀCH CH CH ꢀ). C
2
2
2
2
2
2
NMR, HSQC, HMBC (100 MHz, CDCl
3
) δ=170.0 (CONH), 158.2 (C8), 149.7 (C3),
1
49.4 (C2), 137.8 (C4b), 131.5 (C14b), 131.4 (C8b), 127.9 (C14a), 125.7 (C6), 124.9
3
(C8a), 122.9 (C4a), 122.5 (C7), 115.5 (C5), 115.4 (C1), 108.4 (C4), 55.9 (C ꢀOCH
3
),
2
6
5
5.9 (C ꢀOCH
3
), 55.5 (C ꢀOCH
3
), 39.5 (C1'), 31.2 (C3'), 28.9 (C2'). HRMS–ESI (m/z):
+
[M+H] calcd for C H NO , 380.1862; found: 380.1850.
23
25
4
(
2-(Iodomethyl)pyrrolidin-1-yl)(2,3,6-trimethoxyphenanthren-9-yl)methanone
(9). Compound 9 was synthesized from compound 8 (189.6 mg) via the same
procedure employed to synthesize compound 3. Compound 9 was purified by flash
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6
column chromatography (cyclohexane/EtOAc = 2/1) as a yellow oil (184.4 mg, 73%).
1
H NMR , COSY (600 MHz, CDCl
2.4 Hz, 1H, PhenꢀH5), 7.84 (s, 1H, PhenꢀH10), 7.56 (s, 1H, PhenꢀH4), 7.22 (dd, J =
.9, 2.4 Hz, 1H, PhenꢀH7), 7.21 (s, 1H, PhenꢀH1), 4.34 (d, J = 6.3 Hz, 1H, ꢀCH I),
3
) δ= 7.99 (d, J = 8.9 Hz, 1H, PhenꢀH8), 7.87 (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
8
4
3
2
2
3
2
6
.11 (s, 3H, C ꢀOMe), 4.05–4.02 (m, 4H, C ꢀOMe and Hꢀ2'), 4.01 (s, 3H, C ꢀOMe),
.71 (d, J = 9.3 Hz, 1H, ꢀCH I), 3.39–3.30 (m, 1H, Hꢀ5'), 3.26–3.17 (m, 1H, Hꢀ5'),
2
.31–2.18 (m, 1H, Hꢀ3'), 2.00–1.94 (m, 1H, Hꢀ4'), 1.93–1.87 (m, 1H, Hꢀ3'), 1.81–1.70
13
(
m, 1H, Hꢀ4'). C NMR, HSQC, HMBC (150 MHz, CDCl
3
) δ = 170.0 (CO), 158.4
(
C8), 149.7 (C3), 149.7 (C2), 132.2 (C4b), 131.4 (C14b), 127.5 (C8b), 126.3 (C14a),
24.6 (C6), 122.2 (C8a), 121.9 (C4a), 115.9 (C7), 108.5 (C5), 104.4 (C1), 103.2 (C4),
1
3
2
6
56.1 (C ꢀOCH
4.5 (C4'), 12.3 (ꢀCH
found: 506.0834.
Synthesis of 10a and 10b. In a glove box, a vial was charged with iodide 9 (50.5 mg,
100 ꢁmol) and 1,4ꢀdioxane (1 mL) under argon atmosphere. Pd(PPh (11.6 mg, 10
mol) and K PO (42.4 mg, 200 ꢁmol) were subsequently added. The reaction vessel
3
), 57.1 (C ꢀOCH
3
), 56.0 (C ꢀOCH
3
), 55.6 (C1'), 50.2 (C5'), 31.6 (C2'),
+
2
2
I). HRMS–ESI (m/z): [M+H] calcd for C23
H
24INO
4
, 506.0828;
3 4
)
ꢁ
3
4
was removed from the glove box and heated in oil bath to 100 °C under stirring for 24
h. The reaction mixture was allowed to cool to ambient temperature, quenched with
1N HCl and the aqueous layer was extracted with CH Cl . The combined organic
2
2
2 4
layers were dried with Na SO and concentrated in vacuo to give crude residue, which
was purified by flash column chromatography (cyclohexane/EtOAc = 1/2) to give
lactam 10a (13.9 mg, 37%, yellow solid) and 10b (15.5 mg, 41%, yellow solid).
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2
,3,6-Trimethoxy-12,13,13a,14-tetrahydrodibenzo[f,h]pyrrolo[1,2-b]isoquinolin-9
31
(11H)-one (10a). R
f
= 0.21, SiO
2
, cyclohexane/EtOAc = 1:2. Mp: 253–254 °C (ref,
33
1
Mp: 252–253 °C; ref, Mp: 262–264 °C). H NMR, COSY (400 MHz, CDCl
3
) δ =
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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48
49
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51
52
53
54
55
56
57
58
59
60
9
.32 (d, J = 9.3 Hz, 1H, PhenꢀH8), 7.93 (s, 1H, PhenꢀH4), 7.87 (d, J = 2.6 Hz, 1H,
PhenꢀH5), 7.34 (s, 1H, PhenꢀH1), 7.27 (dd, J =9.3, 2.6 Hz, 1H, PhenꢀH7), 4.15 (s, 3H,
3
2
6
3 3 3
C ꢀOCH ), 4.08 (s, 3H, C ꢀOCH ), 4.04 (s, 3H, C ꢀOCH ), 3.97–3.77 (m, 3H, Hꢀ11,
Hꢀ13), 3.56 (dd, J = 15.6, 4.0 Hz, 1H, Hꢀ14), 2.93 (dd, J = 15.5, 13.4 Hz, 1H, Hꢀ14),
13
2
.55–2.37 (m, 1H, Hꢀ13a), 2.24–2.13 (m, 1H, Hꢀ12), 2.03–1.87 (m, 2H, Hꢀ13).
C
NMR, HSQC, HMBC (100 MHz, CDCl ) δ = 164.3 (CO), 157.7 (C8), 150.1 (C3),
3
1
49.5 (C2), 132.5 (C4b), 131.0 (C14b), 129.6 (C8b), 126.4 (C14a), 124.4 (C6), 123.7
(C8a), 123.6 (C4a), 115.2 (C7), 104.9 (C5), 104.2 (C1), 103.8 (C4), 56.0 (C13a), 55.9
3
2
6
(C ꢀOCH
3 3 3
), 55.5 (C ꢀOCH ), 55.2 (C ꢀOCH ), 45.3 (C11), 33.9 (C14), 32.7 (C13),
3
1
23.6 (C12). Spectral data are in agreement with literature values.
3
,6,7-Trimethoxy-12,13,13a,14-tetrahydrodibenzo[f,h]pyrrolo[1,2-b]isoquinolin-9
31
(11H)-one (10b). R
f
2
= 0.19, SiO , cyclohexane/EtOAc = 1:2. Mp: 200–201 °C (ref,
22d
1
Mp: 200–201 °C; ref, Mp: 195–197 °C). H NMR, COSY (400 MHz, CDCl
3
) δ =
9.05 (s, 1H, Hꢀ8), 8.01 (d, J = 9.2 Hz, 1H, Hꢀ1), 7.89 (d, J = 2.5 Hz, 1H, Hꢀ4), 7.87 (s,
7
1
H, Hꢀ5), 7.24 (dd, J = 9.2, 2.5 Hz, 1H, Hꢀ1), 4.13 (s, 3H, C ꢀOCH
3
), 4.11 (s, 3H,
6
3
C ꢀOCH ), 4.06 (s, 3H, C ꢀOCH ), 3.95–3.78 (m, 3H, Hꢀ11, Hꢀ13), 3.67 (dd, J = 15.7,
3
3
4
.1 Hz, 1H, Hꢀ14), 3.00–2.89 (m, 1H, Hꢀ14), 2.53–2.36 (m, 1H, Hꢀ13), 2.23–2.16 (m,
13
1H, Hꢀ12), 2.02–1.87 (m, 2H, Hꢀ13). C NMR, HSQC, HMBC (100 MHz, CDCl
3
) δ
=
164.7 (CO), 159.3(C3), 149.5 (C7), 148.5 (C6), 134.2 (C4b), 133.1 (C8b), 126.7
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(
C14b), 125.3 (C14a), 124.3 (C1), 123.0 (C8a), 122.0 (C4a), 115.5 (C2), 108.1 (C4),
7
6
1
04.4 (C5), 102.9 (C8), 55.9 (C13a), 55.9 (C ꢀOCH
3
), 55.5 (C ꢀOCH
3
), 55.3
3
(C ꢀOCH
3
), 45.4 (C11), 33.9 (C14), 32.3 (C13), 23.5 (C12). Spectral data are in
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
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7
8
9
0
1
2
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7
8
9
0
31
agreement with literature values.
rac-Antofine (1b). Compound 1b was synthesized from compound 10a (37.7 mg) via
the same procedure employed to synthesize compound 1a. Compound 1b was purified
by flash column chromatography (EtOAc/MeOH = 15/1) as a yellow solid (33.8 mg,
31
22d
1
9
3%). Mp: 211–212 °C. (ref, Mp: 211–212 °C; ref, Mp: 205–207 °C). H NMR,
COSY (400 MHz, CDCl ) δ =7.93 (s, 1H, PhenꢀH4), 7.92 (d, J = 2.6 Hz, 1H,
3
PhenꢀH5), 7.81 (d, J = 9.1 Hz, 1H, PhenꢀH8), 7.32 (s, 1H, PhenꢀH1), 7.22 (dd, J = 9.1,
3
2.6 Hz, 1H, PhenꢀH7), 4.73 (d, J = 14.9 Hz, 1H, Hꢀ9), 4.13 (s, 3H, C ꢀOCH
3
), 4.08 (s,
2
6
3
H, C ꢀOCH
1H Hꢀ11), 3.37 (dd, J = 15.9, 2.6 Hz, 1H, Hꢀ14), 3.04–2.92 (m, 1H, Hꢀ14), 2.61–2.50
m, 2H, Hꢀ13a, H11), 2.33–2.23 (m, 1H, Hꢀ13), 2.14–2.03 (m, 1H, Hꢀ12), 2.03–1.89
3 3
), 4.04 (s, 3H, C ꢀOCH ), 3.77 (d, J = 14.9 Hz, 1H, Hꢀ9), 3.54–3.42 (m,
(
13
(m, 1H, Hꢀ12), 1.88–1.77 (m, 1H, Hꢀ13). C NMR, HSQC, HMBC (100 MHz,
CDCl ) δ = 157.5 (C8), 149.4 (C3), 148.4 (C2), 130.2 (C4b), 126.9 (C14b), 125.4
(C8b), 125.2 (C14a), 124.2 (C6), 124.0 (C8a), 123.6 (C4a), 114.9 (C7), 104.7 (C5),
3
3
2
1
04.0 (C1), 103.8 (C4), 60.3 (C13a), 56.0 (C ꢀOCH
3
), 55.9 (C ꢀOCH
3
), 55.5
6
(C ꢀOCH ), 54.9 (C11), 53.6 (C9), 33.4 (C14), 31.1 (C13), 21.6 (C12). Spectral data
3
31
are in agreement with literature values.
rac-Deoxypergularinine (1c). Compound 1c was synthesized from compound 10b
(37.7 mg) via the same procedure employed to synthesize compound 1a. Compound
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c was purified by flash column chromatography (EtOAc /MeOH = 15/1) as a yellow
3
1
22d
solid (32.7 mg, 90%). Mp: 208–209 °C. (ref, Mp: 209–210 °C; ref, Mp: 225–
1
2
28 °C). H NMR, COSY (400 MHz, CDCl
3
) δ = 7.96 (d, J = 9.0 Hz, 1H, Hꢀ1), 7.93
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
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53
54
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56
57
58
59
60
(
s, 1H, Hꢀ5), 7.91 (d, J = 2.5 Hz, 1H, Hꢀ4), 7.24 (dd, J = 9.0, 2.5 Hz, 1H, Hꢀ2), 7.15 (s,
7
1
H, Hꢀ8), 4.66 (d, J = 14.7 Hz, 1H, Hꢀ9), 4.12 (s, 3H, C ꢀOCH
3
), 4.07 (s, 3H,
6
3
C ꢀOCH
3 3
), 4.04 (s, 3H, C ꢀOCH ), 3.76 (d, J = 14.7 Hz, 1H, Hꢀ9), 3.60–3.49 (m, 1H,
Hꢀ11), 3.45 (dd, J = 16.2, 2.8 Hz, 1H Hꢀ14), 3.00 (1H, dd, J = 16.2, 10.6 Hz, Hꢀ14),
2
.63–2.51 (m, 2H, Hꢀ13a, Hꢀ11), 2.33–2.23 (m, 1H, Hꢀ13), 2.18–2.05 (m, 1H, Hꢀ12),
13
2
.04–1.96 (m, 1H, Hꢀ12), 1.89–1.75 (m, 1H, Hꢀ13). C NMR, HSQC, HMBC (100
) δ = 157.7 (C3), 149.5 (C7), 148.3 (C6), 130.4 (C4b), 126.8 (C8b),
125.4 (C14b), 125.3 (C14a), 125.2 (C1), 123.4 (C8a, C4a), 114.9 (C2), 104.6 (C4),
MHz, CDCl
3
7
6
1
03.9 (C5), 103.0 (C8), 60.2 (C13a), 56.0 (C ꢀOCH
3
), 56.0 (C ꢀOCH
3
), 55.5
3
(C ꢀOCH
3
), 55.0 (C11), 53.6 (C9), 33.1 (C14), 31.1 (C13), 21.6 (C12). Spectral data
31
are in agreement with literature values.
Associated Content
NMR spectra for all compounds and HPLC data of (S)ꢀtylophorine. This material is
available free of charge via the Internet at http://pubs.acs.org.
Author Information
Corresponding Author
*
Eꢀmail: opatz@uniꢀmainz.de
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Notes
The authors declare no competing financial interest.
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Acknowledgements
We thank Nicola Otto and Jens Langhanki (both Mainz) for proofꢀreading of the
manuscript and Dr. Johannes C. Liermann as well as Dr. Norbert Hanold (both Mainz)
for NMR spectroscopy and mass spectrometry. Financial support by the Carl
Zeissꢀfoundation is gratefully acknowledged.
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(
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