Diastereodivergent Synthesis of the Quinolizidine-Indolizidine Alkaloids of the Leontidine/Camoensine Family

Article abstract of DOI:10.1002/ejoc.202100270

Leontidine and camoensine, the main representatives of the small quinolizidine-indolizidine alkaloid subgroup, are characterized by an inner bispidine system to which a 2-pyridone and a pyrrolidine are fused on opposite sides. We efficiently synthesized both natural products from the commercially available and abundant alkaloid cytisine, which was converted into the key intermediate, N-Boc-11-oxocytisine, by iodine oxidation and protection. Grignard addition, Paal-Knorr type cyclization, and hydrogenation delivered endo-pyrrolidine fused leontidine, while the reversed reaction order, viz. reduction, Sakurai allylation, and ring closure, afforded exo-pyrrolidine annulated camoensine. Hydrogenation and deoxygenation of the pyridone moieties provided four further alkaloids, tetrahydroleontidine, camoensidine, 11-epileontidane and leontidane. In addition, the artificial alkaloid isoleontidine, carrying an endo-fused pyrrolidine on the same side as the pyridone, was prepared from C-13 oxidized cytisine.

Full text of DOI:10.1002/ejoc.202100270

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Diastereodivergent Synthesis of the Quinolizidine-
Indolizidine Alkaloids of the Leontidine/Camoensine Family
[a]
[a]
[a]
[a]
Stefan Wagner, Susanne Sigl, Melanie Schenkl, and Matthias Breuning*
In memoriam of Professor Siegfried Hünig.
Leontidine and camoensine, the main representatives of the
small quinolizidine-indolizidine alkaloid subgroup, are charac-
terized by an inner bispidine system to which a 2-pyridone and
a pyrrolidine are fused on opposite sides. We efficiently
synthesized both natural products from the commercially
available and abundant alkaloid cytisine, which was converted
into the key intermediate, N-Boc-11-oxocytisine, by iodine
oxidation and protection. Grignard addition, Paal-Knorr type
cyclization, and hydrogenation delivered endo-pyrrolidine fused
leontidine, while the reversed reaction order, viz. reduction,
Sakurai allylation, and ring closure, afforded exo-pyrrolidine
annulated camoensine. Hydrogenation and deoxygenation of
the pyridone moieties provided four further alkaloids, tetrahy-
droleontidine, camoensidine, 11-epileontidane and leontidane.
In addition, the artificial alkaloid isoleontidine, carrying an endo-
fused pyrrolidine on the same side as the pyridone, was
prepared from C-13 oxidized cytisine.
Introduction
Tri- and tetracyclic (bis)quinolizidine alkaloids (Figure 1) are the
most prominent secondary metabolites in the Papilionoideae
[1,2]
subfamily of the plant family Fabaceae (Leguminosae). These
natural products are all structurally characterized by an inner
bispidine core (3,7-diazabicyclo[3.3.1]nonane, 6), to which
normally combinations of an exo- or endo-piperidine, as in
sparteine (1), lupanine (2), anagyrine (4), and thermopsine (5),
or an oxidized version thereof, such as the 2-piperidone in 2 or
the 2-pyridone in cytisine (3), 4, and 5, are attached on opposite
sides. This structural feature is a consequence of their biosyn-
thesis from three molecules of l-lysine (C N source): two of
5
them form the outer piperidines while the third one completes
[1,3]
the central bispidine core (see arrangement A, n=1).
initially produced metabolites are sparteine (1) and lupanine
2), which get further modified, for example by oxidation,
The
(
degradation, and epimerization, thus setting the basis for the
roughly 200 known (bis)quinolizidine alkaloids.
In addition to the ‘standard’ (bis)quinolizidine alkaloids, a
small number of atypical quinolizidine-indolizidine derivatives
[4]
Figure 1. Natural (bis)quinolizidine alkaloids (1–5), the inner bispidine core 6,
and the rare quinolizidine-indolizidine alkaloids (7–12).
(7–12) exists that possess an exo- or endo-fused pyrrolidine. It
is hypothesized that the smaller ring size results from a
replacement of one molecule of l-lysine by l-ornithine (C N
4
[5]
source) during their biosynthesis. The first member of this
subclass, leontidine (7), was already isolated in 1932 from
[
6]
[7]
Leontice ewersmannii, camoensine (10) and camoensidine
[
a] S. Wagner, S. Sigl, M. Schenkl, Prof. Dr. M. Breuning
Department of Chemistry
[8]
(11), both first extracted from Camoensia maxima, followed in
975. Tetrahydroleontidine (8) and 11-epileontidane (12)
[8d]
[8d]
University of Bayreuth
1
Universitätsstraße 30, 95440 Bayreuth, Germany
E-mail: matthias.breuning@uni-bayreuth.de
http://www.breuning.uni-bayreuth.de/de/index.html
were detected by GC-MS in Maackia amurensis, their only
natural source so far. The fully reduced derivative in the
leontidine row, leontidane (12), has not yet been found in
nature.
The first syntheses of these alkaloids were done in the
context of their (stereo)structure elucidation. Santamaria and
Khuong-Huu prepared camoensidine (11) from lupanine (2) by
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100270
©
2021 The Authors. European Journal of Organic Chemistry published by
Wiley-VCH GmbH. This is an open access article under the terms of the
Creative Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly cited.
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doi.org/10.1002/ejoc.202100270
[
6g]
formal ring contraction (4 steps, 7% yield), while Yunusov’s
route to the quinolizidine-indolizidine alkaloids 7–12 of the
leontidine/camoensine family. Although key intermediate 15
can be prepared from 13 by total synthesis, we searched for a
route from cytisine (3) to leontidine (7) included an unintended
[6e,g]
[12]
epimerization (4 steps, 0.4% yield).
The synthesis of
camoensine (10) by Ohmiya and coworkers is illustrated in
straightforward ex-natural-pool approach. The abundant, com-
mercially available alkaloid cytisine (3), which can be isolated in
good quantities from the seeds of the Golden Rain tree,
[10]
Scheme 1 (bottom). Chlorination of cytisine (3) followed by
HCl elimination furnished the imine 16 in low 40% yield
[11]
[15]
because of regioselectivity issues. Addition of the Grignard
reagent 17 occurred highly diastereoselectively to the less
hindered exo-face of 16, but in low 23% yield, thus giving, after
Laburnum anagyroides, seemed to be an ideal source.
acetal hydrolysis and reductive cyclization, the alkaloid 10 in Results and Discussion
overall 4 steps and meager 8% yield. Furthermore, exo-
configured camoensine (10) and camoensidine (11) were trans-
formed into their endo-counterparts, leontidine (7) and tetrahy-
droleontidine (8), by an oxidation-reduction sequence, but
Our synthesis commenced with the search for a suitable
method that permits an oxidation of the amino function in
cytisine (3) to an amide. Screening of several reagents (e.g.
K Fe(CN) , PhI(OAc) , KMnO ) and optimization of the reaction
[6g]
again in low yields (9–11%). Satisfying yields (>80%) were
3
6
2
4
[16]
solely obtained in the hydrogenations of the pyridone deriva-
conditions revealed iodine as oxidant of choice, which is also
advantageous with regard to environmental aspects. Treatment
of 3 with an excess of iodine (7.5 equivalents) in THF/sat.
[6g]
tives 7 and 10 to the respective piperidones 8 and 11.
We recently presented an effective inside-out approach to
tri- and tetracyclic bisquinolizidine alkaloids that permits access
to more than 25 members of this class in both enantiomeric
NaHCO (1:1) at 70°C delivered a 2:1 mixture of desired 11-
3
[17]
oxocytisine (18), a natural product by itself,
and the
[12–14]
forms (Scheme 1, top).
Key sequences include the reductive
unwanted C-13 oxidation product 19 (Scheme 2). Thus, the
desymmetrization of the bisimide 13 and the transformation of
the resulting dioxobispidine 14 into the α,N-pyridone annulated
tricycle 15. An important stereochemical feature is that the N-
Boc activated lactam function in 15 allows an introduction of
either an endo- or, optionally, an exo-fused ring by a simple
change of the reaction order. Since all nucleophilic attacks on
the carbonyl group in 15 or on related functionalities occur
highly selectively from the less hindered, convex exo-face, a
reduction-organyl addition sequence will install an exo-substitu-
ent (exo-protocol), while the reversed organyl addition-reduc-
tion procedure will generate an endo one (endo-protocol).
Given the ease of stereoselective ring annulation at 15, we
decided to develop the first efficient and diastereodivergent
effect of the fused pyridone on the regioselectivity of the
[18]
oxidation step is just small, which is in good agreement with
[
11]
the results of earlier NCS oxidations of 3 (see Scheme 1).
Since chromatographic separation of the isomers 18 and 19
proved to be tedious, the crude reaction mixture was subjected
to N-Boc protection, which provided, after column chromatog-
raphy or, even more conveniently, after MPLC separation, the
key intermediate 15 in analytically pure form and overall 50%.
The N-Boc lactam 20 was obtained in 25% yield.
The leontidine-type natural products were accessed from 15
by applying the endo-protocol (Scheme 3). Addition of the
functionalized Grignard reagent 17 occurred smoothly at the N-
Boc imide function and delivered, after ring opening of the
primarily resulting hemiaminal during work up, the ketone 21
in high 82% yield. The N-Boc group was cleaved under Lewis
acidic conditions, which triggered a Paal-Knorr type intra-
molecular pyrrole synthesis that afforded the unnatural pyrrolo-
[19,20]
cytisine 22
in a single step and 75% yield. Preferential
hydrogenation of the electron-rich pyrrole in the presence of
the pyridone was achieved with PtO under acidic conditions
2
and a short reaction time. Other catalysts, such as Pd/C,
Pd(OH) /C, Pd(OAc) , Ru/C, RhCl(PPh ) , or Raney-Ni, afforded
2
2
3 3
mixtures of 7 and 8. As expected, hydrogenation exclusively
occurred from the less concave exo-site and solely provided
natural, endo-pyrrolidine fused leontidine (7). Under the same
[
10,12,13]
Scheme 1. Known
and current strategies for the total synthesis of
Scheme 2. Preparation of the key intermediate 15 by oxidation of cytisine
(3) and N-Boc protection.
bisquinolizidine and quinolizidine-indolizidine alkaloids.
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genation afforded the artificial alkaloid isoleontidine (24), a
regioisomer of leontidine (7) with both fused rings on the same
side, in 33% overall yield over three steps.
The members of the camoensine family, 10–12, were
synthesized by using the exo-protocol, which is based on a
reduction-addition sequence (Scheme 5). Reduction of the
lactam 15 and acetalization, as developed earlier in our
[12]
group,
provided the N,O-acetal 25 in high 91% yield. All
attempts to introduce functionalized lithium, magnesium, zinc,
and copper organyls (e.g. 17) to 25 or the iminium species
[22]
derived thereof were met with low success, which parallels
the insufficient yields reached by Ohmiya et al. in their additions
[10]
to the imine 16 (see Scheme 1). To circumvent this problem,
N,O-acetal 25 was converted into the natural alkaloid 11-
[
23,24]
Scheme 3. Synthesis of the endo-pyrrolidine fused quinolizidine-indolizidine
alkaloids 7–9 of the leontidine family.
allylcytisine (26),
(
following a known Sakurai protocol
[12]
85%). The direct hydroamination of 26 to camoensine (10) in
the presence of a catalytic amount of a Rh-phosphine
complex failed, and one-pot protocols such as hydrozircona-
I
[25]
conditions, but at prolonged reaction times, the pyridone
moieties in 22 and 7 were hydrogenated, too, giving the
alkaloid tetrahydroleontidine (8) as the only product and in
tion with the Schwartz reagent cp ZrHCl or hydroboration with
2
BH ·SMe, both followed by a metal/iodine exchange and an
3
intramolecular substitution to close the pyrrolidine, delivered
[26]
high �90% yield. Final reduction of 8 with LiAlH afforded
10 in just low yields (<20%). By far more efficient was a two-
step sequence: Hydroboration of 26 with 9-BBN and subse-
4
leontidane (9), an alkaloid which has not yet been found in
nature.
[27]
quent oxidation afforded selectively the terminal alcohol 27,
which was subjected to hydroxy/bromide exchange under
Appel conditions providing, after in-situ ring closure under HBr
elimination, the desired natural product camoensine (10) in
good 68% yield over two steps. Hydrogenation of 10 over PtO2
under acidic conditions delivered camoensidine (11), which was
Submission of the C-13 oxidized cytisine derivative 20 to
the addition-cyclization sequence described above delivered
[21]
the tetracyclic pyrrolo alkaloid 23 (Scheme 4). Mild hydro-
reduced with LiAlH to give the third natural alkaloid in this
4
row, 11-epileontidane (12).
We finally tested the alkaloids 7–12, 15, 18–22, and 25–27,
on their activity against the cancer lines U87 (glioblastoma),
5
18A2 (melanoma), and HCT116 (colon cancer), but no notice-
able cytotoxicity (MTT assay, IC50 (72 h) <50 μM) was observed.
Scheme 4. Synthesis of the artificial alkaloid isoleontidine (24).
Conclusion
We successfully developed an efficient route to the quinolizi-
dine-indolizidine alkaloids 7–12. Key intermediate was N-Boc
activated 11-oxocytisine (15), which was accessed in 50% yield
by iodine oxidation and protection of the commercially
available alkaloid cytisine (3). Grignard addition, Paal-Knorr type
cyclization, exo-hydrogenation, and reduction afforded the
three endo-pyrrolidine annulated alkaloids leontidine (7), tetra-
hydroleontidine (8), and leontidane (9) in a row (3–4 steps, 55–
3
8% yield). Their exo-pyrrolidine fused counterparts, camoen-
sine (10), camoensidine (11), and 11-epileontidane (12), were
prepared from 15 in 4–6 steps and 53–28% yield by reduction,
exo-selective Sakurai allylation, ring closure, and adjustment of
the oxidation state in the original pyridone moiety. In addition,
the artificial alkaloid isoleontidine 24, a regioisomer of 7 that
carries an 13,N-fused pyrrolidine, was synthesized from the C-13
oxidized cytisine derivative 20.
Scheme 5. Synthesis of the exo-pyrrolidine fused quinolizidine-indolizidine
alkaloids 10–12 of the camoensine family.
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Experimental Section
sine (20): Colorless crystals; yield: 785 mg (2.53 mmol, 25%); R =
f
25
0
.54 (CH Cl /MeOH 95:5); m.p. 172–175°C; [α] =À 399.4 (c=1.0,
2
2
D
All reactions with moisture-sensitive reagents were carried out
under argon atmosphere in anhydrous solvents, prepared using
1
MeOH); H NMR (CDCl , 500 MHz): δ=7.29 (dd, J=9.0 Hz, 7.0 Hz, 1
3
H, 4-H), 6.52 (d, J=9.2 Hz, 1 H, 3-H), 6.29 (d, J=6.8 Hz, 1 H, 5-H),
[28]
standard procedures. Commercially available reagents (highest
quality available) were used as received. Reactions were monitored
by thin layer chromatography on precoated silica gel (Merck TLC
Silica gel 60 F254). Spots were visualized by UV light (254 nm) or by
4
1
1
1
1
1
.22 (d, J=15.7 Hz, 1 H, 10-HH), 3.96 (dd, J=15.7 Hz, 6.4 Hz, 1 H,
0-HH), 3.86 (dd, J=13.3 Hz, 5.7 Hz, 1 H, 11-HH), 3.76 (m, 2 H, 7-H,
1-HH), 2.88 (s, 1 H, 9-H), 2.28 (d, J=13.3 Hz, 1 H, 8-HH), 2.13 (d, J=
13
3.2 Hz, 1 H, 8-HH), 1.49 (s, 9 H, C(CH ) ) ppm; C NMR (CDCl3,
3
3
staining with aqueous KMnO , vanillin, or Dragendorff’s reagent.
4
25 MHz): δ=167.9 (C-13), 163.5 (C-2), 152.0 (CO N), 142.7 (C-6),
2
Silica gel (Macherey-Nagel, particle size 40–63 μm) was used for
column chromatography. Melting points were measured on a
Thermo Scientific 9300 melting point apparatus. Optical rotations
were recorded on a Jasco P-1020 polarimeter (10 cm cell) and are
39.3 (C-4), 119.0 (C-3), 107.2 (C-5), 84.1 (C(CH ) ), 52.5 (C-11), 49.6
3
3
(
C-10), 45.8 (C-7), 28.1 (C(CH ) ), 25.8 (C-9), 23.1 (C-8) ppm; IR (ATR):
3 3
~
v=2985, 1719, 1696, 1650, 1576, 1544, 1367, 1273, 1256, 1136,
À 1
+
790 cm ; HRMS (ESI): m/z calcd for C H N O +H : 305.15015 [M
1
6
20
2
4
3
À 1
À 1
given in units of degcm g dm . NMR spectra were taken on a
Bruker Avance III HD 500 instrument and calibrated using the
residual undeuterated solvent as an internal reference. All signal
+
+
H] ; found: 305.14828.
(7R,9R)-N-Boc-9-(aminomethyl)-7-(4,4-dimethoxybutanoyl)-
6,7,8,9-tetrahydro-4H-quinolizin-4-one (21): The Grignard reagent
17 was freshly prepared from 3-bromo-1,1-dimethoxypropane
(518 μL, 705 mg, 3.85 mmol), which was added to Mg (85.1 mg,
1
13
assignments in the H and C NMR data were made on basis of 2D
NMR spectra (COSY, HSQC, HMBC). Infrared spectra were recorded
on a PerkinElmer Spectrum 100 FT-IR spectrometer, high resolution
mass spectra on a ThermoFisher Scientific Q-Exactive (Orbitrap)
mass spectrometer using ESI (electrospray ionization). The alkaloid
cytisine (3), which is also commercially available, was isolated from
the seeds of Laburnum anagyroides following ref. [15]. For reasons
of consistency, all tri- and tetracyclic alkaloids prepared are
numbered following the standard alkaloid numbering (for details,
see Supporting Information).
3.50 mmol) and I (catalytic amount) in anhydr. THF (10 mL). The
2
reaction mixture was refluxed for 60 min and then cooled to rt. This
Grignard reagent was added dropwise at 0°C to a solution of the
N-Boc imide 15 (366 mg, 1.20 mmol) in THF (11 mL). After 2 h, sat.
aq. NH Cl (50 mL) was added and the reaction mixture was
4
successively extracted with CH
CH Cl (3×50 mL). The combined organic layers were dried over
Na SO , evaporated, and the residue was purified by column
Cl /MeOH (90:10, 2×50 mL) and
2
2
2
2
2
4
Oxidation of cytisine (3): Cytisine (3; 2.00 g, 10.5 mmol), dissolved
chromatography (SiO , CH Cl /MeOH 100:0!95:5) to give ketone
2
2
2
in THF (300 mL) and H O (120 mL), was treated with I (20.0 g,
2
2
2
1 as a colorless oil; yield: 402 mg (986 μmol, 82%); R =0.41
f
25 1
7
8.8 mmol) and NaHCO (8.82 g, 105 mmol). After 5 h at 70°C, the
3
(
CH Cl /MeOH 95:5); [α] =À 110.7 (c=0.5, MeOH); H NMR
2
2
D
reaction mixture was cooled to rt, and sat. aq. Na S O (120 mL) and
sat. aq. Na CO (200 mL) were added. The organic solvent THF was
2
2
3
(
CDCl , 500 MHz, 9:1 mixture of rotamers, *=isolated signal of the
3
2
3
minor rotamer): δ=7.27 (dd, J=9.2 Hz, 6.9 Hz, 1 H, 4-H), 6.46 (d, J=
removed under vacuum and the remaining aqueous layer was
exhaustively extracted with CH Cl /MeOH (4:1, 20×100 mL) and,
9
4
4
.1 Hz, 1 H, 3-H), 6.10 (d, J=6.8 Hz, 1 H, 5-H), 4.83 (m, 0.9 H, NH),
.66 (m, 0.1 H, NH*), 4.58 (m, 0.1 H, 10-HH*), 4.44 (dd, J=14.4 Hz,
.8 Hz, 0.9 H, 10-HH), 4.34 (t, J=5.4 Hz, 1 H, CH(OCH ) ), 4.00 (dd,
2
2
after addition of NH (aq., 25%, 30 mL), with CH Cl (15×100 mL)
3
2
2
3
2
and CHCl (5×100 mL). Evaporation of the solvent delivered a 2:1
3
J=14.3 Hz, 8.7 Hz, 0.9 H, 10-HH), 3.78 (m, 0.1 H, 10-HH*), 3.54 (dt,
mixture of crude 18 and 19 (2.14 g). CH Cl (100 mL) was added
and the slurry was treated with Boc O (5.73 g, 26.3 mmol), NEt
2
2
J=14.0 Hz, 6.3 Hz, 1 H, NHCHH), 3.31 (s, 3 H, OCH ), 3.29 (s, 3 H,
3
2
3
OCH ), 3.28 (m, 1 H, NHCHH), 3.08 (m, 0.9 H, 7-H), 3.00 (m, 1.1 H, 9-
3
(
4.37 mL, 3.19 g, 31.5 mmol), and DMAP (128 mg, 1.05 mmol) at rt.
H, 7-H*), 2.62 (td, J=7.1 Hz, 2.7 Hz, 2 H, COCH ), 2.17 (dt, J=
2
After 19 h, sat. aq. NH Cl (200 mL) was added and the reaction
4
1
1
3.7 Hz, 7.2 Hz, 1 H, 8-HH), 1.90 (m, 2 H, COCH CH ), 1.77 (dt, J=
2 2
13
mixture was extracted with CH Cl2 (3×200 mL). The combined
organic layers were dried over Na SO , evaporated, and the residue
2
3.7 Hz, 8.8 Hz, 1 H, 8-HH), 1.43 (s, 9 H, C(CH ) ) ppm; C NMR
3
3
2
4
(CDCl , 125 MHz): δ=209.0 (COCH ), 163.1 (C-2), 156.0 (CO N), 147.6
3
2
2
was purified by MPLC [Grace Reveleris apparatus, SiO2 cartridge
80 g), CH Cl /MeOH 100:0!80:20] to give the N-Boc imides 15
C-6), 138.9 (C-4), 117.7 (C-3), 104.3 (C-5), 103.8 (CH(OCH ) ), 80.0
3 2
(
2
2
3 3 3 3 2
and 20 in analytically pure form each. Purification and separation of
1
0), 38.1 (C-7), 36.1 (COCH ), 28.5 (C(CH ) ), 26.7 (COCH CH ), 25.3
2 3 3 2 2
1
5 and 20 by column chromatography (SiO , CH Cl /MeOH 100:0!
2
2
2
~
(
1
C-8) ppm; IR (ATR): v=2935, 1707, 1653, 1545, 1366, 1271, 1251,
165, 1127, 1057, 797, 732 cm ; HRMS (ESI): m/z calcd for
95:5) is also possible, but more tedious. Analytically pure samples
À 1
of 18 and 19 were obtained from the intermediate mixture of 18
and 19 by repeated column chromatography (SiO , CH Cl /MeOH
+
+
C H N O +Na : 431.21526 [M+Na] ; found: 431.21402.
2
1
32
2
6
2
2
2
1
00:0!95:5). 11-Oxocytisine (18): All characterization data were
Pyrrolocytisine 22: A solution of ketone 21 (565 mg, 1.39 mmol) in
anhydr. CH Cl (20 mL) was slowly treated with BF ·OEt (878 μL,
in full agreement with those reported in ref. [12]. 13-Oxocytisine
2
2
3
2
(
9
19): Colorless crystals. R =0.23 (CH Cl /MeOH/NH (aq., 25%)
5:4.5:0.5); m.p. 255–260°C (decomp.); [α] = +138.4 (c=1.0,
984 mg, 6.93 mmol) at 0°C. After 1 h at 0°C and 1 h at rt, MeOH/
f
2
2
3
28
D
NH (aq., 25%; 9:1, 2 mL) was added and stirring was continued for
3
1
MeOH); H NMR (CDCl , 500 MHz): δ=7.26 (m, 1 H, 5-H), 6.63 (s, 1 H,
NH), 6.46 (d, J=9.1 Hz, 1 H, 3-H), 6.24 (d, J=6.8 Hz, 1 H, 4-H), 4.10
10 min. The crude reaction mixture was directly subjected to
3
column chromatography (SiO
99:0.9:0.1!95:4.5:0.5) to give 22 as colorless crystals; yield:
236 mg (1.04 mmol, 75%); R =0.42 (CH Cl /MeOH 95:5); m.p. 202–
,
2
CH
Cl
2
/MeOH/NH
2
(aq., 25%)
3
(
d, J=15.9 Hz, 1 H, 10-HH), 4.02 (dd, J=15.9 Hz, 6.8 Hz, 1 H, 10-HH),
.67 (dd, J=12.4 Hz, 5.1 Hz, 1 H, 11-HH), 3.57 (s, 1 H, 7-H), 3.36 (d,
J=12.4 Hz, 1 H, 11-HH), 2.78 (s, 1 H, 9-H), 2.22 (dm, J=13.2 Hz, 1 H,
3
f
2
2
[29]
25
204°C {ref. [19]: 225–226°C}
;
[α]
=À 120.3 (c=0.5, MeOH)
D
13
[29]
1
8-HH), 2.10 (dm, J=13.2 Hz, 1 H, 8-HH) ppm; C NMR (CDCl3,
{ref. [19]: [α]
D
À 113.5 (c=1.5, MeOH)} . H NMR (CDCl
, 500 MHz):
3
1
25 MHz): δ=169.6 (C-13), 163.5 (C-2), 143.8 (C-6), 139.2 (C-5), 118.5
δ=7.27 (dd, J=9.0 Hz, 6.9 Hz, 1 H, 4-H), 6.44 (m, 1 H, 12-H), 6.42
(m, 1 H, 5-H), 6.15 (d, J=6.9 Hz, 1 H, 3-H), 6.12 (t, J=3.1 Hz, 1 H, 14-
H), 5.97 (m, 1 H, 13-H), 4.33 (dm, J=14.5 Hz, 1 H, 10-HH), 4.28 (dd,
J=11.9 Hz, 4.2 Hz, 1 H, 16-HH), 4.10 (dm, J=11.9 Hz, 1 H, 16-HH),
3.75 (dd, J=14.5 Hz, 4.5 Hz, 1 H, 10-HH), 3.69 (m, 1 H, 9-H), 3.44 (m,
1 H, 7-H), 2.21 (dm, J=13.0 Hz, 1 H, 8-HH), 2.16 (dm, J=13.0 Hz, 1
(C-3), 106.7 (C-4), 49.8 (C-10), 48.5 (C-11), 42.9 (C-7), 24.7 (C-9), 22.9
(
C-8) ppm; IR (ATR): ~v =3237, 2925, 1651, 1567, 1544, 1490, 1362,
À 1
+
1
2
146,782 cm ; HRMS (ESI): m/z calcd for C H N O +H :
11 12 2 2
+
05.09715 [M+H] ; found: 205.09700. N-Boc-11-oxocytisine (15):
Colorless crystals; yield: 1.59 g (5.22 mmol, 50%); R =0.35 (CH Cl /
MeOH/NH (aq., 25%) 95:4.5:0.5). All characterization data were in
full agreement with those reported in ref. [12]. N-Boc-13-oxocyti-
f
2
2
1
3
H, 8-HH); C NMR (CDCl
, 125 MHz): δ=163.5 (C-2), 149.1 (C-6),
3
3
138.8 (C-4), 130.6 (C-11), 118.9 (C-12), 118.1 (C-5), 109.0 (C-14), 106.2
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Full Papers
doi.org/10.1002/ejoc.202100270
(
C-3), 105.1 (C-13), 53.8 (C-16), 52.6 (C-10), 33.8 (C-7), 27.4 (C-9), 24.5
Leontidane (9): Tetrahydroleontidine (8; 30.0 mg, 128 μmol) was
(
C-8); ppm; IR (ATR): ~v =2939, 1651, 1573, 1544, 1345, 1316, 1139,
dissolved in anhydr. THF (6 mL) and cooled to 0°C. LiAlH (2.4 M in
4
À 1
+
8
[
00, 709 cm ; HRMS (ESI): m/z calcd for C H N O+H : 227.11789
THF, 425 μL, 1.02 mmol) was added and the reaction mixture was
14
14
2
+
M+H] ; found: 227.11717.
refluxed for 19 h. At rt, sat. aq. Na SO (15 mL) was added dropwise
2
4
until gas evolution ceased. The aqueous layer was extracted with
General hydrogenation procedure: A mixture of the pyridone (7,
Et O (5×10 mL), and the combined organic layers were dried over
2
1
0, 22, or 23) and PtO2 (10 mol%) in AcOH (5 mL/200 μmol
Na SO and concentrated under reduced pressure. The residue was
2
4
pyridone) was hydrogenated at rt and 1 bar H2 pressure. The
reaction mixture was filtered through a pad of celite and the filter
cake was thoroughly washed with CH Cl /MeOH (80:20, 25 mL/
dissolved in aq. HCl (4 M, 15 mL) and extracted with hexanes
15 mL) and Et O (15 mL). The organic layers were discarded. The
(
2
2
2
aqueous layer was basified (pH=14) with aq. NaOH (6.0 M, 15 mL)
2
00 μmol pyridone). After evaporation of the solvent, the crude
and extracted with Et O (3×15 mL). The combined organic layers
2
product was dissolved in aq. NaOH (20 mL/200 μmol pyridone) and
were dried over Na SO and the solvent was removed under
2
4
extracted with CH Cl2 (5×5 mL/200 μmol pyridone). The organic
2
vacuum to give the alkaloid leontidane (9) as a colorless oil (note:
this compound slowly decomposes upon exposure to air); yield:
layer was dried over Na SO4 and the solvent was removed in
2
vacuum. Column chromatography ((deactivated) SiO2, CH Cl /
2
2
1
9
6
1
9.5 mg (88.5 μmol, 69%); R =0.15 (CH Cl /MeOH/NH (aq., 25%)
f
2
2
3
MeOH/NH3 (aq., 25%) 100:0:0!95:4.5:0.5) afforded the hydro-
25
0:9:1); [α] = +17.8 (c=0.1, MeOD) {ref. [6c]: [α] = +16.5 (c=
D
1
D
genated product.
.1, EtOH)}; H NMR (MeOD, 500 MHz): δ=3.23 (d, J=11.3 Hz, 1 H,
6-HH), 3.04 (m, 1 H, 14-HH), 2.98 (d, J=11.8 Hz, 1 H, 10-HH), 2.78
Leontidine (7): Following the general hydrogenation procedure,
the pyrrole 22 (98.5 mg, 435 μmol) was hydrogenated for exactly
(d, J=10.7 Hz, 1 H, 2-HH), 2.20 (d, J=11.9 Hz, 1 H, 10-HH), 2.13 (m,
2
2
H, 11-H, 16-HH), 2.05 (d, J=11.3 Hz, 1 H, 6-H), 1.88–1.73 (m, 7 H,
-HH, 3-HH, 5-HH, 8-HH, 9-H, 13-HH, 14-HH), 1.68–1.49 (m, 7 H, 4-
2
.25 h. Work up and chromatography afforded, besides small
amounts of 22 (7%) and 8 (9%), the natural alkaloid leontidine (7)
HH, 5-HH, 7-H, 8-HH, 12-H , 13-HH), 1.43–1.33 (m, 2 H, 3-HH, 4-HH);
as colorless crystals; yield: 72.3 mg (314 μmol, 72%); R =0.29
2
f
1
3
(
CH Cl /MeOH/NH (aq., 25%) 95:4.5:0.5); m.p. 120–122°C {re-
C NMR (MeOD, 125 MHz): δ=68.7 (C-11), 68.1 (C-6), 58.9 (C-2),
6.4 (C-10), 55.4 (C-14), 53.7 (C-16), 37.3 (C-8), 36.5 (C-7), 33.2 (C-9),
1.4 (C-4), 27.8 (C-12), 26.1 (C-3), 26.0 (C-5), 21.6 (C-13) ppm; IR
2
2
3
[
29]
30
f. [6a,6b,6c,6e]: 116–120°C; ref. [6g]: 145°C }; [α] =À 170.5 (c=
5
3
D
[30]
1
[
.22, MeOH)
{ref. [6b]: [α] =À 188.7 (c=1.7, MeOH); ref. [6c]:
D
(
ATR): ~v =2928, 2857, 2755, 2719, 1463, 1442, 1332, 1279, 1117,
α] =À 192.2 (c=1.7, MeOH); ref. [6e]: [α] =À 186.5 (c=1.22,
D
D
À 1
1
[
3
1
]
1
102, 1064, 1042, 802, 734 cm ; HRMS (ESI): m/z calcd for C H N
H : 221.20123 [M+H] ; found: 221.20081.
MeOH); ref. [6 g]: [α] =À 180}; H NMR (CDCl , 500 MHz): δ=7.25
14 24
2
D
3
+
+
+
(
m, 1 H, 4-H), 6.42 (d, J=9.0 Hz, 1 H, 3-H), 5.96 (d, J=6.8 Hz, 1 H, 5-
H), 4.04 (d, J=15.7 Hz, 1 H, 10-HH), 3.73 (dd, J=15.7 Hz, 7.0 Hz, 1 H,
0-HH), 3.06 (d, J=10.3 Hz, 1 H, 16-HH), 2.93 (s, 1 H, 7-H), 2.82 (m, 1
H, 14-HH), 2.37 (m, 1 H, 9-H), 2.33 (dm, J=10.3 Hz, 1 H, 16-HH), 2.12
Pyrrolocytisine 23: The reaction sequence 20!23 was performed
in analogy to the sequence 7!21!22 described above. Treatment
of a solution of the N-Boc imide 20 (101 mg, 332 μmol) in anhydr.
THF (3 mL) with 17 (0.29 M in THF, 3.43 mL, 996 μmol), prepared
from 3-bromo-1,1-dimethoxypropane (299 μL, 406 mg, 2.22 mmol)
and Mg (49.0 mg, 2.02 mmol) in anhydr. THF (7 mL), afforded, after
aqueous work up, the crude addition product (158 mg), which was
directly subjected to deprotection and cyclization by treatment
with BF OEt (210 μL, 230 mg, 1.66 mmol) in anhydr. CH Cl (5 mL).
1
(
m, 1 H, 11-H), 1.99 (m, 2 H, 14-HH, 8-HH), 1.81–1.58 (m, 5 H, 8-HH,
13
1
1
1
1
2-H , 13-H ); C NMR (CDCl , 125 MHz): δ=164.0 (C-2), 152.1 (C-6),
2 2 3
38.7 (C-4), 116.7 (C-3), 104.6 (C-5), 67.9 (C-11), 60.1 (C-16), 53.9 (C-
4), 44.3 (C-10), 35.3 (C-7), 29.6 (C-9), 27.5 (C-8), 26.8 (C-12), 20.9 (C-
À 1
3) ppm; IR (ATR): ~v =2935, 2784, 1651, 1570, 1547, 1341, 798 cm ;
+
+
HRMS (ESI): m/z calcd for C H N O+H : 231.14919 [M+H] ;
14
18
2
*
3
2
2
2
found: 231.14860.
After work up and column chromatography (SiO , CH Cl /MeOH/
2
2
2
NH3 (aq., 25%) 100:0:0!95:4.5:0.5), the pyrrolocytisine 23 was
Tetrahydroleontidine (8) from 7: Following the general hydro-
genation procedure, leontidine (7; 50.0 mg, 217 μmol) was hydro-
genated for 20 h. Work up and chromatography (deactivated SiO2)
delivered the natural alkaloid tetrahydroleontidine (8) as a yellowish
resin which partially crystallized upon standing; yield: 46.3 mg
obtained as a colorless resin; yield: 34.9 mg (154 μmol, 46%); R =
f
2
5
0
0
6
9
1
.48 (CH Cl /MeOH/NH (aq., 25%) 97:2.7:0.3); [α] =À 192.0 (c=
2
2
3
D
1
.5, MeOH); H NMR (CDCl , 500 MHz): δ=7.24 (dd, J=9.0 Hz,
3
.9 Hz, 1 H, 4-H), 6.55 (dd, J=2.4 Hz, 1.7 Hz, 1 H, 13-H), 6.38 (dd, J=
.0 Hz, 1.1 Hz, 1 H, 3-H), 6.10 (m, 2 H, 5-H, 14-H), 5.94 (dd, J=3.4 Hz,
.6 Hz, 1 H, 15-H), 4.30 (dd, J=16.1 Hz, 8.4 Hz, 1 H, 10-HH), 4.21 (dd,
(
9
[
198 μmol, 91%); Rf =0.28 (CH Cl /MeOH/NH
(aq., 25%)
2
2
3
]
:
5:4.5:0.5); m.p. 60–64°C {ref. [19 : 62.5–64.5°C; ref. [6g] 62–67°C};
26
D
J=12.4 Hz, 4.5 Hz, 1 H, 11-HH), 4.12 (s, 1 H, 7-H), 4.07 (d, J=12.4 Hz,
H, 11-HH), 3.95 (d, J=16.1 Hz, 1 H, 10-HH), 2.95 (m, 1 H, 9-H), 2.21
α] =À 44.3 (c=1.0, MeOH) {ref. [19]: [α] =À 45.3 (c=4.4, EtOH);
D
1
1
ref. [6 g]: [α] =À 46}; H NMR (MeOD, 500 MHz): δ=4.74 (dt, J=
D
1
3
(dm, J=12.9 Hz, 1 H, 8-HH), 2.14 (dm, J=12.9 Hz, 1 H, 8-HH);
C
1
2
3
3.9 Hz, 2.0 Hz, 1 H, 10-HH), 3.59 (m, 1 H, 6-H), 3.35 (dt, J=11.4 Hz,
.0 Hz, 1 H, 16-HH), 2.88 (m, 1 H, 14-HH), 2.71 (dd, J=13.9 Hz,
.6 Hz, 1 H, 10-HH), 2.32 (m, 1 H, 3-HH), 2.23 (m, 1 H, 3-HH), 2.12
NMR (CDCl , 125 MHz): δ=163.6 (C-2), 149.9 (C-6), 139.4 (C-4), 129.2
3
(
5
(
7
C-16), 120.1 (C-13), 117.2 (C-3), 109.0 (C-14), 105.0 (C-15), 104.0 (C-
), 52.1 (C-11), 48.5 (C-10), 34.1 (C-7), 26.4 (C-9), 24.2 (C-8) ppm; IR
ATR): ~v =2935, 1653, 1572, 1542, 1494, 1280, 1142, 1053, 803, 749,
(
dd, J=11.4 Hz, 2.5 Hz, 1 H, 16-HH), 2.07 (m, 1 H, 11-H), 1.96 (dm,
J=12.5 Hz, 1 H, 8-HH), 1.91–1.77 (m, 6 H, 4-HH, 5-H , 8-HH, 9-H, 14-
HH), 1.73 (m, 1 H, 7-H), 1.70–1.58 (m, 5 H, 4-HH, 12-H , 13-H );
2
À 1
+
1
3
21 cm ; HRMS (ESI): m/z calcd for C H N O+H : 227.11845 [M+
14 14 2
+
C
2
2
H] ; found: 227.11812.
NMR (MeOD, 125 MHz): δ=171.5 (C-2), 68.6 (C-11), 60.6 (C-6), 55.1
(
(
C-14), 53.9 (C-16), 42.3 (C-10), 35.8 (C-8), 35.4 (C-7), 33.7 (C-3), 32.2
Isoleontidine (24): Following the general hydrogenation procedure,
pyrrole 23 (40.9 mg, 181 μmol) was hydrogenated for 3.5 h. Work
up and chromatography afforded the non-natural alkaloid isoleonti-
C-9), 28.5 (C-5), 28.0 (C-12), 21.8 (C-13), 20.7 (C-4) ppm; IR (ATR): ~v =
À 1
2
932, 2777, 1622, 1547, 1445, 1351, 1256, 1163, 1101 cm ; HRMS
+
+
(ESI): m/z calcd for C H N O+H : 235.18049 [M+H] ; found:
14 22 2
dine (24) as a colorless resin; yield: 24.2 mg (105 μmol, 58%); R =
f
2
35.18058.
25
1
0
(
.31 (CH Cl /MeOH 95:5); [α] =À 186.6 (c=0.5, MeOH); H NMR
2
2
D
CDCl , 500 MHz): δ=7.25 (dd, J=8.9 Hz, 7.0 Hz, 1 H, 4-H), 6.44 (d,
Tetrahydroleontidine (8) from 22: Following the general hydro-
genation procedure, pyrrole 22 (53.6 mg, 237 μmol) was hydro-
genated for 18 h, giving, after work up and chromatography
3
J=8.3 Hz, 1 H, 3-H), 5.83 (d, J=6.5 Hz, 1 H, 5-H), 3.97 (d, J=15.4 Hz,
1
1
2
H, 10-HH), 3.88 (dd, J=15.4 Hz, 7.0 Hz, 1 H, 10-HH), 3.08 (d, J=
0.4 Hz, 1 H, 11-HH), 2.87 (m, 2 H, 7-H, 13-HH), 2.44 (s, 1 H, 9-H),
.28 (d, J=10.5 Hz, 1 H, 11-HH), 2.09 (m, 1 H, 16-H), 2.00 (m, 2 H, 8-
(deactivated SiO ), tetrahydroleontidine (8) as a colorless resin;
2
yield: 50.0 mg (213 μmol, 90%). All characterization data were
identical to those given above.
HH, 13-HH), 1.78 (m, 1 H, 8-HH), 1.66 (m, 1 H, 15-HH), 1.55 (m, 2 H,
Eur. J. Org. Chem. 2021, 2498–2505
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13
1
4-H ), 1.44 (m, 1 H, 15-HH); C NMR (CDCl , 125 MHz): δ=164.1 (C-
(6.0 M; 3 mL) and extracted with CH Cl (5×12 mL). The organic
2 2
2
3
2
), 147.7 (C-6), 137.7 (C-4), 117.0 (C-3), 107.7 (C-5), 67.3 (C-16), 59.4
layers were combined and dried over Na SO. Removal of the
solvent under vacuum and column chromatography (deactivated
2
(
(
1
C-11), 53.7 (C-13), 50.6 (C-10), 37.6 (C-7), 28.0 (C-9), 27.3 (C-8), 27.0
C-15), 20.6 (C-14) ppm; IR (ATR): ~v =2932, 2782, 1651, 1568, 1547,
367, 1347, 1142, 800 cm ; HRMS (ESI): m/z calcd for C H N O+
SiO , CH Cl /MeOH/NH (aq., 25%) 98:1.8:0.2!90:9.1:0.9) afforded
2
2
2
3
À 1
the natural alkaloid camoensine (10) as a colorless oil; yield:
87.4 mg (379 μmol, 84%); R =0.23 (CH Cl /MeOH/NH (aq., 25%)
14
18
2
+
+
H : 231.14919 [M+H] ; found: 231.14881.
f
2
2
3
2
4
20
9
(
5:4.5:0.5); [α]D =À 113.1 (c=0.5, CHCl ) {ref. [10]: [α] =À 112.9
3
D
N-Boc-11-methoxycytisine (25): According to ref. [12], a solution of
the N-Boc imide 15 (307 mg, 1.01 mmol) in anhydr. MeOH (30 mL)
c=0.5, CHCl ); ref. [4e]: [α] =À 108 (c=1.0, CHCl ); ref. [6g]: [α] =
3
D
3
D
[29]
1
À 186} ; H NMR (CDCl , 500 MHz): δ=7.27 (dd, J=9.0 Hz, 7.0 Hz, 1
3
was treated with NaBH (114 mg, 3.03 mmol) at 0°C and stirred for
4
H, 4-H), 6.42 (d, J=9.0 Hz, 1 H, 3-H), 6.00 (d, J=6.6 Hz, 1 H, 5-H),
9
0 min at this temperature. Methanolic HCl (2.0 M; 2.83 mL) was
4
1
.17 (d, J=15.3 Hz, 1 H, 10-HH), 3.88 (dd, J=15.3 Hz, 6.2 Hz, 1 H,
0-HH), 2.99 (tm, J=8.7 Hz, 1 H, 11-H), 2.92 (s,1 H, 7-H), 2.75–2.63
added and the reaction mixture was allowed to reach rt over 4 h.
Sat. aq. NaHCO (20 mL) was added and the solvent was removed
under vacuum. The aqueous layer was extracted with CH Cl (5×
3
(
m, 4 H, 14-H , 16-H ), 2.48 (s, 1 H, 9-H), 2.00–1.87 (m, 2 H, 8-HH, 13-
2 2
13
2
2
HH), 1.83–1.60 (m, 4 H, 8-HH, 12-H , 13-HH); C NMR (CDCl3,
2
2
5 mL) and the combined organic layers were dried over Na SO .
2 4
1
25 MHz): δ=163.7 (C-2), 150.9 (C-6), 138.9 (C-4), 116.9 (C-3), 105.0
Column chromatography (SiO , CH Cl /MeOH 100:0!95:5) deliv-
2
2
2
(C-5), 66.1 (C-11), 55.0 (C-14 or C-16), 54.9 (C-14 or C-16), 51.8 (C-
ered the N,O-acetal 25 as a colorless resin; yield: 295 mg (921 μmol,
1%; ref. [12]: 90%). All characterization data were in full agree-
ment with those reported in ref. [12].
1
0), 35.0 (C-7), 29.0 (C-9), 25.2 (C-12), 21.3 (C-13), 20.8 (C-8) ppm; IR
9
À 1
(
ATR): ~v =2949, 2873, 1648, 1565, 1547, 1163, 1142, 800, 734 cm ;
+
+
HRMS (ESI): m/z calcd for C H N O+H : 231.14919 [M+H] ;
1
4
18
2
1
3
found: 231.14842. The C NMR data are in full agreement with
those reported for synthetic 10 in ref. [10]. For detailed
comparison of our NMR data with literature NMR data of isolated
1
1-Allylcytisine (26): According to ref. [12], allyltrimethylsilane
a
(390 μL, 281 mg, 2.46 mmol) and BF ·OEt2 (156 μL, 175 mg,
3
1
.23 mmol) were added at 0°C to a solution of the N,O-acetal 25
[4e,6g]
1
0,
see Supporting Information.
(
132 mg, 410 μmol) in anhydr. CH Cl (6 mL). After 16 h at rt, the
crude mixture was adsorbed to a small amount of silica and
subjected to column chromatography (SiO , CH Cl /MeOH/NH (aq.,
2 2
Camoensidine (11): Following the general hydrogenation proce-
dure, camoensine (10, 90.7 mg, 394 μmol) was hydrogenated for
2
2
2
3
2
5%) 100:0:0!90:9.1:0.9) to give 11-allylcytisine (26) as a white
1
5 h. Work up and chromatography (deactivated SiO ) delivered the
2
solid; yield: 80.0 mg (347 μmol, 85%; ref. [12]: 93%). All character-
ization data were in full agreement with those reported in
refs. [10,12,23a,23c,23d].
natural alkaloid camoensidine (11) as a pale yellow oil; yield:
7
9
3.1 mg (312 μmol, 79%); R =0.27 (CH Cl /MeOH/NH (aq., 25%)
f 2 2 3
27
0:9:1); [α] =À 72.5 (c=1.13, EtOH) {ref. [6g]: [α] =À 67; ref. [4a]:
D
D
2
7
1
[
α]D =À 73 (c=1.13, EtOH)}; H NMR (CDCl , 500 MHz): δ=4.57 (d,
1
1-(3-Hydroxypropyl)cytisine (27): 9-BBN (0.5 M in THF, 1.21 mL,
3
05 μmol) was slowly added at 0°C to a solution of 11-allylcytisine
J=13.1 Hz, 1 H, 10-HH), 3.34 (t, J=7.0 Hz, 1 H, 6-H), 2.73 (m, 2 H,
6
(
1
4-HH, 16-HH), 2.63 (d, J=13.1 Hz, 1 H, 10-HH), 2.43–2.20 (m, 5 H, 3-
2
26; 69.5 mg, 302 μmol) in anhydr. THF (7 mL). The mixture was
H , 11-H, 14-HH, 16-HH), 2.02 (m, 1 H, 5-HH), 1.94 (s, 1 H, 9-H), 1.85–
refluxed for 5 h and cooled to rt. Aq. H O (30 wt%, 7 mL,
2
2
1
.68 (m, 6 H, 4-HH, 7-H, 8-HH, 12-H , 13-HH), 1.63–1.45 (m, 3 H, 4-
2
13
6
8.5 mmol) and aq. NaOCl (5 wt% active Cl, 7 mL, 10.0 mmol) were
HH, 8-HH, 13-HH), 1.35 (d, J=12.5 Hz, 1 H, 5-HH); C NMR (CDCl3,
added and stirring was continued for 2 h. Aq. NaOH (6 M, 3.5 mL)
was added and the aqueous layer was extracted with CH Cl (20×9
1
1
1
1
25 MHz): δ=171.4 (C-2), 64.6 (C-11), 60.1 (C-6), 54.5 (C-14), 49.4 (C-
6), 47.6 (C-10), 33.2 (C-3), 33.2 (C-7), 31.2 (C-9), 28.9 (C-8), 27.6 (C-
2), 27.6 (C-5), 21.1 (C-4), 20.1 (C-13) ppm; IR (ATR): ~v =2945, 2866,
2
2
mL). The combined organic layers were dried over Na SO and
concentrated under reduced pressure. The residue was purified by
column chromatography (SiO2, CH Cl /MeOH/NH (aq., 25%)
2
4
À 1
619, 1442, 1253, 1163, 1018, 916, 726, 641 cm ; HRMS (ESI): m/z
2
2
3
+
+
calcd for C H N O+H : 235.18049 [M+H] ; found: 235.18016. For
1
00:0:0!90:9:1), providing the alcohol 27 as a colorless resin;
14 22
2
a detailed comparison of our NMR data with literature NMR data of
yield: 61.1 mg (246 μmol, 81%); R =0.14 (CH Cl /MeOH/NH (aq.,
f
2
2
3
[4a,e]
25
1
isolated 11,
see Supporting Information.
2
5
9
5%) 95:4.5:0.5); [α]D =À 74.0 (c=1.0, MeOH); H NMR (CDCl3,
00 MHz): δ=7.29 (dd, J=9.0 Hz, 6.9 Hz, 1 H, 4-H), 6.44 (dd, J=
.0 Hz, 1.0 Hz, 1 H, 3-H), 5.99 (dd, J=6.8 Hz, 0.7 Hz, 1 H, 5-H), 4.14
1
1-Epileontidane (12): Camoensidine (11; 62.7 mg, 268 μmol) was
dissolved in anhydr. THF (4 mL) and cooled to 0°C. LiAlH (2.4 M in
4
(d, J=15.8 Hz, 1 H, 10-HH), 3.89 (dd, J=15.8 Hz, 6.5 Hz, 1 H, 10-HH),
THF, 893 μL, 2.14 mmol) was added and the reaction mixture was
3
.68 (ddd, J=11.0 Hz, 5.5 Hz, 4.2 Hz, 1 H, CHHOH), 3.54 (ddd, J=
1.0 Hz, 8.0 Hz, 3.0 Hz, 1 H, CHHOH), 3.32 (br. s, 2 H, NH, OH), 3.26
refluxed for 23 h. At rt, sat. aq. Na SO (8 mL) was added dropwise
2
4
1
until gas evolution ceased. The aqueous layer was extracted with
(dd, J=13.4 Hz, 2.4 Hz, 1 H, 13-HH), 2.94 (d, J=10.1 Hz, 1 H, 11-H),
Et O (5×8 mL), and the combined organic layers were dried over
2
2
.86 (s, 1 H, 7-H), 2.75 (dt, J=13.4 Hz, 2.1 Hz, 1 H, 13-HH), 2.22 (d,
Na SO and concentrated under reduced pressure. The residue was
2
4
J=2.5 Hz, 1 H, 9-H), 2.15 (d, J=13.3 Hz, 1 H, 8-HH), 1.99 (m, 1 H,
CHH(CH ) OH), 1.89–1.74 (m, 2 H, 8-HH, CHHCH OH), 1.69–1.54 (m, 2
dissolved in aq. HCl (1 M, 15 mL) and extracted with hexanes
15 mL) and Et O (15 mL). The organic layers were discarded. The
2
2
2
(
13
2
H, CHH(CH ) OH, CHHCH OH); C NMR (CDCl , 125 MHz): δ=163.7
2
2
2
3
aqueous layer was basified (pH=14) with aq. NaOH (6.0 M, 15 mL)
(C-2), 150.5 (C-6), 139.2 (C-4), 117.1 (C-3), 105.2 (C-5), 62.9 (CH OH),
2
and extracted with Et O (3×15 mL). The combined organic layers
2
5
9.4 (C-11), 51.1 (C-10), 47.3 (C-13), 35.2 (C-7), 32.0 (C-9), 31.6
were dried over Na SO and the solvent was removed under
2
4
(
CH CH OH), 29.5 (CH (CH ) OH), 21.3 (C-8) ppm; IR (ATR): ~v =2932,
2
2
2
2 2
vacuum to give the natural alkaloid 11-epileontidane (12) as a pale
yellow oil (note: this compound slowly decomposes upon exposure
to air); yield: 39.4 mg (179 μmol, 67%); R =0.23 (CH Cl /MeOH/NH
3
À 1
+ +
2
236, 1645, 1544, 1356, 1144, 1059, 909, 796, 723 cm ; HRMS (ESI):
m/z calcd for C H N O +H : 249.15975 [M+H] ; found:
14
20
2
2
f
2
2
2
49.15971.
25
1
(
5
aq., 25%) 90:9:1); [α]D = +23.2 (c=1.0, MeOH); H NMR (MeOD,
00 MHz): δ=2.87 (m, 1 H, 6-H), 2.84–2.70 (m, 4 H, 2-HH, 10-HH, 14-
HH, 16-HH), 2.64 (m, 2 H, 2-HH, 10-HH), 2.24 (dd, J=10.9 Hz, 2.4 Hz,
H, 16-HH), 1.98–1.86 (m, 5 H, 5-HH, 7-H, 11-H, 13-HH, 14-HH), 1.79
m, 2 H, 3-HH, 4-HH), 1.68 (m, 3 H, 3-HH, 8-HH, 13-HH), 1.63–1.51 (m,
Camoensine (10): A solution of the alcohol 27 (112 mg, 451 μmol)
in anhydr. CH Cl (5 mL) was treated at 0°C with CBr (329 mg, 992
2
2
4
1
(
3
μmol), NEt (81.3 μL, 59.3 mg, 586 μmol), and PPh (213 mg, 812
3
3
μmol). After 18 h at rt, the reaction mixture was quenched with aq.
1
3
H, 8-HH, 9-H, 12-HH), 1.39–1.28 (m, 3 H, 4-HH, 5-HH, 12-HH); C
HCl (0.5 M, 7 mL). The organic layer was separated and the aqueous
layer was extracted with CH Cl2 (7 mL). The organic layers were
discarded. The aqueous layer was basified (pH=14) with aq. NaOH
NMR (MeOD, 125 MHz): δ=67.4 (C-11), 65.9 (C-6), 63.5 (C-16), 58.1
C-14), 55.4 (C-2), 50.6 (C-10), 35.8 (C-9), 33.6 (C-7), 31.1 (C-12), 29.6
2
(
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(
C-3), 29.1 (C-5), 26.4 (C-8), 26.0 (C-13), 22.1 (C-4) ppm; IR (ATR): ~v =
A. D. Kuzovkov, P. S. Massagetov, J. Gen. Chem. USSR 1953, 23, 921–926;
À 1
Zh. Obshch. Khim. 1953, 23, 880–886; d) G. Gresser, P. Bachmann, L.
Witte, F. C. Czygan, Biochem. Syst. Ecol. 1993, 21, 679–685; e) S.
Iskandarov, R. A. Shaimardanov, S. Y. Yunusov, Chem. Nat. Compd. 1971,
2
931, 2758, 1442, 1347, 1265, 1142, 1116, 1072 cm ; HRMS (ESI):
m/z calcd for C H N +H : 221.20123 [M+H] ; found: 221.20079.
+
+
14
24
2
7, 611–614; Khim. Prir. Soedin. 1971, 631–636; f) E. G. Tkeshelashvili, K. S.
Mudzhiri, Chem. Nat. Compd. 1975, 11, 823; Khim. Prir. Soedin. 1975, 11,
8
2
07; g) J. Santamaria, F. Khuong-Huu, Phytochemistry 1975, 14, 2501–
Acknowledgements
504.
[
6g]
[
7] Camoensine (10) was isolated from Camoensia maxima, C. brevica-
[4e]
We gratefully thank Prof. Rainer Schobert and Sofia Bär for the
cytotoxicity measurements. Open access funding enabled and
organized by Projekt DEAL.
lyx, and Daphniphyllum oldhami (ref. a), and detected by GC-MS in
[6d] [6d] [4b]
Leontice ewersmannii, L. leontopetalum, Orphanodendron bernalii,
[
4b]
O. grandiflorum, and diverse Melolobium species (ref. b): a) S.-Z. Mu,
J.-S. Wang, X.-S. Yang, H.-P. He, C.-S. Li, Y.-T. Di, Y. Wang, Y. Zhang, X.
Fang, L.-J. Huang, X.-J. Hao, J. Nat. Prod. 2008, 71, 564–569; b) B. E.
van Wyk, G. H. Verdoorn, L. Burger, R. Greinwald, S. Afr. J. Bot. 1988, 54,
3
86–388.
Conflict of Interest
[6g]
[4a]
[
8] Camoensidine (11) was isolated from Camoensia maxima,
brevicalyx,
detected by GC-MS in Orphanodendron bernalii, O. grandiflorum,
Sakoanala villosa (ref. e), Poecilanthe parviflora (ref. f), P. subcordata
C.
[
4e]
Maackia amurensis (ref. a–d), and4b]M. tashiroi,
and
[
[4b]
The authors declare no conflict of interest.
(
ref. f), P. itapuana (ref. f), Lupinus latifolius (ref. g), and L. sericeus (ref. g):
a) K. Saito, S. Tsai, S. Ohmiya, H. Kubo, H. Otomasu, I. Murakoshi, Chem.
Pharm. Bull. 1986, 34, 3982–3985; b) K. Saito, T. Yoshino, T. Sekine, S.
Ohmiya, H. Kubo, H. Otomasu, I. Murakoshi, Phytochemistry 1989, 28,
Keywords: Alkaloids · Asymmetric synthesis · Bispidine ·
Cytisine · Quinolizidine
2533–2534; c) Y.-H. Wang, J.-S. Li, Z.-R. Jiang, H. Kubo, K. Higashiyama, S.
Ohmiya, Chem. Pharm. Bull. 2000, 48, 641–645; d) A. D. Kinghorn, M. F.
Balandrin, L. J. Lin, Phytochemistry 1982, 21, 2269–2275; e) B. E. van Wyk,
R. Greinwald, L. Witte, Biochem. Syst. Ecol. 1993, 21, 711–714; f) R.
Greinwald, P. Bachmann, G. Lewis, L. Witte, F.-C. Czygan, Biochem. Syst.
Ecol. 1995, 23, 547–553; g) M. Wink, C. Meissner, L. Witte, Phytochemistry
[
1] a) G. Boschin, D. Resta, in: Natural Products: Phytochemistry, Botany and
Metabolism of Alkaloids, Phenolics and Terpenes (Eds.: K. G. Ramawat, J.-
M. Merillon), Springer-Verlag, Berlin, Heidelberg, 2013, pp. 381–403;
b) S. Ohmiya, K. Saito, I. Murakoshi, in: The Alkaloids: Chemistry and
Physiology, Vol. 47 (Ed.: G. A. Cordell), Academic Press: New York, 1995,
pp. 1–114; c) K. Saito, I. Murakoshi, in: Studies in Natural Product
Chemistry (Ed.: Atta-ur-Rahman), Elsevier, 1995, pp. 519–549.
2] a) M. Lourenço, P. Máximo, L. M. Ferreira, M. M. A. Pereira, in: Studies in
Natural Products Chemistry: Bioactive Natural Products, Part H (Ed.: Atta-
ur-Rahman), Elsevier, Amsterdam, New York, 2002, pp. 233–298; b) K. A.
Aslanov, Y. K. Kushmuradov, A. S. Sadykov, in: The Alkaloids: Chemistry
and Physiology, Vol. 31 (Ed.: A. Brossi), Academic Press, 1987, pp. 117–
1
995, 38, 139–153.
[
9] The intermediate of this synthesis, 11-allylcytisine (26), was treated with
HI at 230°C. With leontidine (7) being formed, epimerization at C-11
must have occurred under the harsh conditions, see ref. [10].
[
[
[
10] H. Kubo, S. Ohmiya, I. Murakoshi, Can. J. Chem. 1994, 72, 214–217.
11] Y.-H. Wang, K. Higashiyama, H. Kubo, J.-S. Li, S. Ohmiya, Heterocycles
2
000, 53, 545–548.
12] D. Scharnagel, J. Goller, N. Deibl, W. Milius, M. Breuning, Angew. Chem.
018, 130, 2456–2460; Angew. Chem. Int. Ed. 2018, 57, 2432–2435.
13] J. Goller, C. B. Hübschle, M. Breuning, Eur. J. Org. Chem. 2019, 2019, 895–
99.
[
[
[
2
1
92; c) A. D. Kinghorn, M. F. Balandrin, in: Alkaloids: Chemical and
Biological Perspectives, Vol. 2 (Ed.: S. W. Pelletier), John Wiley & Sons,
New York, 1984, pp. 105–141; d) T. Robinson in Molecular Biology,
Biochemistry and Biophysics Molekularbiologie, Biochemie und Biophysik,
Springer-Verlag, Berlin, Heidelberg, 1981, pp. 67–75; e) F. Bohlmann, D.
Schumann, in: The Alkaloids: Chemistry and Physiology (Ed.: R. H. F.
Manske), Academic Press, New York, 1967, pp. 175–221; f) N. J.
Leonhard, in: The Alkaloids: Chemistry and Physiology, Vol. 3 (Eds.: R. H. F.
Manske, H. L. Holmes), Academic Press: New York, 1953, pp. 119–199.
3] a) K. M. Frick, L. G. Kamphuis, K. H. M. Siddique, K. B. Singh, R. C. Foley,
Front. Plant Sci. 2017, 8, 87; b) S. Bunsupa, M. Yamazaki, K. Saito, Front.
Plant Sci. 2012, 3, 239; c) M. Wink, Planta Med. 1987, 53, 509–514.
8
14] For the synthesis of artificial bispidines and 9-oxabispidines by our
group see: a) D. Scharnagel, A. Müller, F. Prause, M. Eck, J. Goller, W.
Milius, M. Breuning, Chem. Eur. J. 2015, 21, 12488–12500; b) M.
Breuning, D. Hein, Eur. J. Org. Chem. 2013, 7575–7582; c) M. Breuning,
D. Hein, M. Steiner, V. H. Gessner, C. Strohmann, Chem. Eur. J. 2009, 15,
12764–12769; d) M. Breuning, M. Steiner, C. Mehler, A. Paasche, D. Hein,
J. Org. Chem. 2009, 74, 1407–1410; e) M. Breuning, M. Steiner,
Tetrahedron: Asymmetry 2008, 19, 1978–1983; f) M. Breuning, A.
Paasche, M. Steiner, S. Dilsky, V. H. Gessner, C. Strohmann, B. Engels, J.
Mol. Struct. 2011, 1005, 178–185.
[
[
4] At least six further natural quinolizidine-indolizidine derivatives are
known or proposed, the camoensidine-11-N-oxide (ref. a), guianoden-
drine (10-oxo-2,3-dehydroleontidine, ref. b, c), an isomer of camoensi-
dine (ref. e), 12α-hydroxycamoensine (ref. e), 12α-hydroxycamoensidine
[15] A. J. Dixon, M. J. McGrath, P. O’Brien, Org. Synth. 2006, 83, 141–154.
[16] For the oxidation of cyclic amines to lactams with iodine, see: R. J.
Griffiths, G. A. Burley, E. P. A. Talbot, Org. Lett. 2017, 19, 870–873.
[17] I. Murakoshi, H. Kubo, M. Ikram, M. Israr, N. Shafi, S. Ohmiya, H.
Otomasu, Phytochemistry 1986, 25, 2000–2002.
(
ref. e, and 12-hydroxy-16-methoxy-11:12,13:14-tetradehydrocamoen-
sine (ref. e): a) S. Ohmiya, H. Kubo, Y. Nakaaze, K. Saito, I. Murakoshi, H.
Otomasu, Chem. Pharm. Bull. 1991, 39, 1123–1125; b) G. C. Kite, Biochem.
Syst. Ecol. 2017, 73, 47–49; c) G. C. Kite, D. Cardoso, N. C. Veitch, G. P.
Lewis, S. Afr. J. Bot. 2013, 89, 176–180; d) A. El-Shazly, T. Sarg, A. Ateya,
E. Abdel Aziz, L. Witte, M. Wink, Pharmazie 1996, 51, 768–772; e) P. G.
Waterman, D. F. Faulkner, Phytochemistry 1982, 21, 215–218.
[18] We also tested the oxidation of N-Boc protected cytisine, speculating
that the attached pyridone might induce a preferred orientation of the
N-Boc group, which, in turn, might favor a regioselective oxidation. All
oxidants tested (I , K Fe(CN) , PIDA, KMnO , RuO ·H O/NaIO ), however,
2
3
6
4
2
2
4
failed to produce any oxidation products.
19] J.-S. Hsu, A. D. Kuzovkov, J. Gen. Chem. USSR 1963, 33, 2012–2015; Zh.
Obshch. Khim. 1963, 33, 2067–2070.
[
5] Currently, it cannot be fully excluded that the quinolizidine-indolizidine
alkaloids are biosynthetically derived from the corresponding bisquino-
lizidine alkaloids by contraction of the fused piperidine to a pyrrolidine.
The genus Maackia, however, one source of these alkaloids, is known to
produce both, quinolizidine and indolizidine natural products in
parallel, which supports, at least for this genus, a mixed biosynthesis
from l-lysine and l-ornithine, see ref. [8b,8c] and: J. P. Michael, Nat.
Prod. Rep. 2001, 18, 520–542.
[
[
20] According to ref. [19], pyrrolocytisine 22 had been prepared earlier by
dehydrogenation of leontidine (7) over Pd/asbestos at 270–300°C. The
melting point and optical rotation given, however, significantly differ
from ours.
[
21] The lower yield in the transformation of 20 to 23, as compared to the
analogous conversion of 15 to 22 (46% vs. 62%, see Scheme 3), might
be a consequence of an interfering retro-Claisen type fragmentation at
the stage of the intermediate hemiaminal. This would be in analogy to
[
6] Leontidine (7) was isolated from Leontice ewersmannii (ref. a–d), L.
albertii (ref. e), L. smirnowii (ref. f), and Camoensia maxima (ref. g): a) A.
Oryekhov, R. Konovalova, Arch. Pharm. Ber. Dtsch. Pharm. Ges. 1932, 270,
a side reaction occurring in the NCS-oxidation of cytisine (3), as
3
29–334; b) S. Yunusov, L. G. Sorokina, J. Gen. Chem. USSR 1949, 19,
[11]
proposed by Ohmiya et al.
.
A427–A435; Zh. Obshch. Khim. 1949, 19, 1955–1963; c) T. F. Platonova,
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[
[
22] For the successful twofold addition of a functionalized zinc organyl into
related bispidine bis-N,O-acetal under Lewis acid catalysis, see
[27] 9-BBN was used to ensure excellent terminal regioselectivity. The
oxidative cleavage of the CÀ B bond proceeded sluggishly under
standard conditions (NaOH, H ), but good results were obtained with
a NaOCl/H mixture.
a
ref. [12].
2 2
O
23] The tricyclic alkaloid 11-allylcytisine (26) was extracted from Sophora
secundiflora (ref. a), Clathrotropis brachypetala (ref. b), Bolusanthus
speciosus (ref. c), and Lupinus princei (ref. d), and detected by GC-MS in
more than 15 other species: a) W. J. Keller, M. Hatfield, Phytochemistry
2 2
O
[28] Purification of Laboratory Chemicals, Eds.: W. L. F. Armarego, D. D. Perrin,
4th ed., Butterworth-Heinemann, Oxford, 2000.
[29] This literature value significantly differs from ours (and other literature
values).
1
979, 18, 2068–2069; b) G. M. Hatfield, W. J. Keller, J. M. Rankin, J. Nat.
Prod. 1980, 43, 164–167; c) K. Asres, J. D. Phillipson, P. Mascagni,
Phytochemistry 1986, 25, 1449–1452; d) K. Asres, Egypt. J. Pharm. Sci.
[30] The optical rotation measured by us is somewhat lower than all other
literature values. We re-measured the optical rotation several times
with the same result and ensured that our compound was analytically
pure.
1996, 37, 1–10.
[
24] For earlier syntheses of 11-allylcytisine (26) see ref. [6e,10,12] and: F.
1
Bohlmann, E. Winterfeldt, H. Overwien, H. Pagel, Chem. Ber. 1962, 95,
[31] The H NMR data given in ref. [6e] [δ=7.04 (q), 6.12 (d), 5.75 (d), 4.03
9
44–948.
25] Z. Liu, J. F. Hartwig, J. Am. Chem. Soc. 2008, 130, 1570–1571.
26] Oxymercuration-reduction (Hg(OAc) ; NaBH ) of 26 provided camoen-
sine (10), the product of an initial anti-Markovnikov addition, in up to
0% yield. Markovnikov products with an internal OH group were not
detected, indicating reversible oxymercuration step. Main side
(m) ppm] do not match with ours.
[
[
2
4
4
a
reaction, which caused us to abandon this sequence, was an
epimerization at C-11 leading to 11-endo-allylcytisine in up to 33%,
most likely through a CÀ N oxidation-reduction sequence (see ref. [6 g]).
Manuscript received: March 3, 2021
Revised manuscript received: April 6, 2021
Accepted manuscript online: April 16, 2021
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© 2021 The Authors. European Journal of Organic Chemistry published
by Wiley-VCH GmbH