Concise total synthesis of dihydrocorynanthenol, protoemetinol, protoemetine, 3-epi-protoemetinol and emetine

Article abstract of DOI:10.1002/ejoc.201101296

A concise asymmetric assembly of secologanine tryptamine and dopamine alkaloids by means of a one-pot three-component cascade reaction methodology is disclosed. This is demonstrated by the expeditious total syntheses of (-)-dihydrocorynanthenol, (-)-protoemetinol, (-)-protoemetine, (-)-3-epi-protoemetinol, and emetine (3-6 steps). The biomimetic synthetic strategy involved the following key steps: (i) One-pot three-component highly enantioselective catalytic Michael/Pictet-Spengler/lactamization cascade reactions; (ii) One-pot tandem Swern oxidation/Wittig sequences; (iii) One-pot tandem hydrogenation sequences. Copyright

Full text of DOI:10.1002/ejoc.201101296

FULL PAPER
DOI: 10.1002/ejoc.201101296
Concise Total Synthesis of Dihydrocorynanthenol, Protoemetinol,
Protoemetine, 3-epi-Protoemetinol and Emetine
Shuangzheng Lin,[a,b] Luca Deiana,[a,b] Abrehet Tseggai,[a,b] and Armando Córdova*[a,b,c]
Keywords: Organocatalysis / Asymmetric catalysis / Multicomponent reactions / Total synthesis / Natural products /
Alkaloids
A concise asymmetric assembly of secologanine tryptamine
thetic strategy involved the following key steps: (i) One-pot
and dopamine alkaloids by means of a one-pot three-compo- three-component highly enantioselective catalytic Michael/
nent cascade reaction methodology is disclosed. This is dem- Pictet–Spengler/lactamization cascade reactions; (ii) One-pot
onstrated by the expeditious total syntheses of (–)-dihydroco-
rynanthenol, (–)-protoemetinol, (–)-protoemetine, (–)-3-epi-
protoemetinol, and emetine (3–6 steps). The biomimetic syn-
tandem Swern oxidation/Wittig sequences; (iii) One-pot tan-
dem hydrogenation sequences.
tal synthesis has also been accomplished on a case-by-case
basis. With respect to more general synthetic strategies of
secologanine alkaloids, the laboratories of Cook[18] and
Martin[19] have disclosed the preparation of (Ϯ)-secologan-
ine tryptamine alkaloids. Recently, Williams and English
developed a general strategy for the synthesis of both types
of dopamine and tryptamine derived alkaloids in racemic
form.[20] Tietze have disclosed an elegant combinatorial
strategy for the synthesis of secologanine dopamine alka-
loids such as emetine 5d through ruthenium-catalyzed
asymmetric hydrogenation.[21] In the realms of organocata-
lysis, Itoh and co-workers reported the catalytic asymmetric
Introduction
Secologanine glucoside 1 is the common biosynthetic
precursor for several structurally diverse alkaloids,[1] which
exhibit analgesic,[2] antiallergenic,[3] anti-inflammatory,[4]
antibacterial[5] and antiviral activities.[6] Among them, seco-
loganine dopamine and tryptamine alkaloids are two dif-
ferent types of natural products (Figure 1).[7] The (S)-deace-
tyl synthase-catalyzed Pictet–Spengler transformation be-
tween dopamine 2 and secologanine 1 gives the former class
of natural products, whereas the strictodine synthase-cata-
lyzed reaction between tryptamine 3 and 1 gives the latter
class of natural products.[8,9] In this context, dihydrocoryn-
anthenol (4a),[10] protoemetinol (5a),[11] protoemetine
(5c),[12] and emetine (5d)[13] are natural products with bio-
logical activity (Figure 1). For example, emetine (5d) exhib-
its antiprotozoic activity[14] and could be useful in the treat-
ment of lymphatic leukemia.[15] In addition, its structural
analogue, tubolosine, exhibits antitumor activity.[16] Thus,
the secologanine dopamine and tryptamine types of alka-
loids have attracted significant interest from the synthetic
community. However, most of the approaches that have
been developed have delivered the compounds in racemic
form, and the asymmetric versions have employed starting
materials from the chiral pool.[10–13,17] Traditionally, the to-
[a] Department of Organic Chemistry,
The Arrhenius Laboratory, Stockholm University,
106 91 Stockholm, Sweden
[b] The Berzelii Center EXSELENT, Stockholm University,
106 91 Stockholm, Sweden
Fax: +46-8-154-908
E-mail: acordova@organ.su.se
armando.cordova@miun.se
[c] Department of Natural Sciences,
Engineering and Mathematics, Mid Sweden University,
851 70 Sundsvall, Sweden
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101296.
Figure 1. Secologanin tryptamine and dopamine alkaloids.
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Synthesis of Secologanine Tryptamine and Dopamine Alkaloids
synthesis of ent-(+)-dihydrocorynanthenol (4a) in four steps ested in developing a general one-pot methodology for the
using a seven day, proline-catalyzed domino Mannich/ total synthesis of these classes of natural products. Herein,
Michael transformation as the key step.[22]
we report the use of a highly enantioselective three-compo-
Multicomponent and domino reactions that involve the nent catalytic asymmetric tandem Michael/Pictet–Spengler/
formation of multiple C–C and C–hetero atom bonds and lactamization reaction as the common starting point for the
stereocenters in one-pot is an important research field concise total syntheses of (–)-dihydrocorynanthenol, (–)-
within organic synthesis.[23] They include “green chemistry” protoemetinol, (–)-protoemetine, (–)-3-epi-protoemetinol,
parameters such as reduction of synthetic steps, waste, and and emetine by one-pot methodologies.
solvents.[24] However, the development of catalytic asym-
metric multicomponent and domino reactions is more chal-
Results and Discussion
lenging.[25] In this context, catalytic construction of quinol-
izidine core structures through domino sequences were re-
cently disclosed.[26–28] Based on the biological activity of
secologanine dopamine and tryptamine alkaloids and on
Synthetic Plan
Retrosynthetic analysis suggested several strategies that
our research interest in the development of multicomponent could be used to generate the alkaloids 4 and 5 [Equations
reactions and asymmetric syntheses,[29] we became inter- (1–4)]. For example, conjugate addition of butanal to alk-
(1)
(2)
(3)
(4)
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A. Córdova et al.
FULL PAPER
ylidene malonate 6 using chiral amine 7 as the catalyst by formed using Swern’s conditions.[33] It is noteworthy that
our recently disclosed methodology would give aldehyde 8 this oxidation step gave quinolizidine aldehyde derivative 19
[Equation (1)].[30] Next, reacting chiral aldehyde 8 with with a chlorine at the C-6 position (8:1 dr) when excess
amines 3 or 2 through reductive amination, lactamization, oxalyl chloride was used as the reactant.[34] If desired, alka-
and decarboxylation would give the precursor of the corre- loid 19 can serve as a valuable precursor for the generation
sponding alkaloid 4 or 5, compound 9, respectively. An- of chlorinated secologanine tryptamine alkaloids. Thus, we
other alternative would be to use chiral aldehyde 10a as the reduced the amount of oxalyl chloride to generate alkaloid
starting material and then react it with the amine compo- 20 in 87% yield. Subsequent Wittig reaction gave the corre-
nents 2 or 3 by Wu’s recently reported Pictet–Spengler/lact- sponding olefin 21 in more than 99% yield. The final one-
amization cascade sequence to give intermediates 12a pot hydrogenation of 21 completed the total synthesis of
[Equation (2)].[27a] The catalytic construction of the quinol- (–)-dihydrocorynanthenol (4a; 86% yield).[35] Thus, we have
izidine core can also be accomplished by using the pro- achieved a five-step enantioselective synthesis of (–)-dihy-
cedure developed by Franzén and co-workers [Equa- drocorynanthenol (4a) starting from enal 13a.
tion (3)].[28,31] Thus, chiral amine ent-7-catalyzed Michael
reaction between enal 13 and amides 14 followed by one-
Total Syntheses of Protoemetinol (5a), (–)-Protoemetine
(5c), and Emetine (5d)
pot acid-mediated Pictet–Spengler cyclization of aminol 15
was used to give the corresponding intermediates 12. How-
ever, this procedure has only been reported for cinnamic
aldehydes 13 as acceptors. According to our retrosynthetic
analysis, the shortest route to intermediate 12a would be
a one-pot, three-component catalytic asymmetric Michael/
Pictet–Spengler/lactamization cascade sequence employing
aliphatic enal 13a, malonate, and either tryptamine 3 or do-
pamine 2 derivatives as the substrates and chiral amine ent-
7 as the catalyst [Equation (4)]. Next, synthetic precursor
12a could be readily elaborated to alkaloids 4 or 5, respec-
tively.
After completion of the concise assembly of dihydrocoryn-
anthenol (4a), we began investigating the total synthesis of
protoemetinol (5a). Thus, we investigated the one-pot three-
component cascade reaction sequence between enal 13a,
malonate, and dopamine derivative 2a. However, the Pictet–
Spengler product was not observed in this case and the
Michael adduct 10a was formed as the predominant prod-
uct [Equation (5)]. To promote the Pictet–Spengler reaction
step, the employment of other acids (e.g., HCl, BF3·Et2O
and formic acid) was investigated; however, no cyclization
occurred. Thus, the imine intermediate 22 is not reactive
enough under these commonly used Pictet–Spengler condi-
tions.
Total Synthesis of (–)-Dihydrocorynanthenol (4a)
We embarked on the total syntheses of alkaloids 4 and 5
by investigating the one-pot, three-component cascade reac-
tion sequence between enal 13a, malonate, and tryptamine
3. Thus, first, malonate was added to enal 13a in the pres-
ence of catalyst ent-7 (10 mol-%). After complete conver-
(5)
1
sion of 13a into aldehyde 10a (as determined by H NMR
analysis of the crude reaction mixture), amine 3 and tri-
fluoroacetic acid (TFA) were added and the reaction mix-
ture was heated to reflux for 16 h at 50 °C (Scheme 1).[32]
To our delight, the multicomponent cascade reaction gave
the corresponding quinolizidine derivative 16a, which was
isolated as a single diastereoisomer in good yield and high
enantioselectivity (47% yield, Ͼ20:1 dr, 92% ee). We were
also able to isolate other diastereoisomers of 16 in 18%
yield. The dr was 72:18:9:1 (16a/16b/16aЈ/16bЈ) as deter-
Because iminium intermediates are more reactive in these
1
mined by H NMR analysis of the crude reaction mixture. types of transformations, we decided to investigate the use
The relative stereochemistry of diastereoisomers 16 were de- of the N-Boc protected dopamine derivative 2b as the amine
termined by NOE NMR experiments. Thus, the one-pot component (Scheme 2).[36] Thus, we envisioned a one-pot,
cascade reaction proceeds with a good α/β ratio (81:19) and three-component catalytic asymmetric tandem Michael/
high anti/syn ratio (90:10). In addition, the β-diastereomeric Pictet–Spengler/lactamization sequence in which aldehyde
precursor 17 was also isolated in 18% yield. By compari- 10a, generated in situ, would condense with amine 2b to
son, performing the reaction according to Equation (2),[27a] form the reactive iminium intermediate 23 and allow the
using TFA as the acid mediator, gave 16a in lower yield and formation of the desired product 24. To our delight, the
lower α/β and anti/syn ratios as well as a slight decrease of one-pot reaction was successful and the corresponding
the ee. The total synthesis was continued by reduction of quinolizidine derivatives 24aЈ and 24b were formed in a 3:1
16a with LiAlH4 (LAH) to give the corresponding alcohol ratio as the predominant diastereoisomers, together with
18a in 70% yield. Oxidation of alcohol 18a was next per- 24bb. Isolation by silica gel column chromatography gave
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Synthesis of Secologanine Tryptamine and Dopamine Alkaloids
give olefin 26a in 71% yield. The final one-pot hydrogena-
tion of 26a completed the total synthesis of (–)-protoemeti-
nol (5a; 72% yield). Thus, the synthesis of the complex nat-
ural product was completed in only four isolation steps. De-
termination of the ee of 5a showed that it was more than
99%. The optical purification had possibly occurred during
the work-up and isolation by recrystallization. We next
completed the total synthesis of (–)-protoemetine (5c) in
75% yield by using the Swern conditions (Scheme 3). It is
noteworthy that protometine 5c serves as an important pre-
cursor for a diverse range of biologically active natural
products (e.g., emetine, cephaeline, and tubolosine), which
can be prepared by the Pictet–Spengler reaction with dopa-
mine 2 and tryptamine derivatives 3, respectively. This was
exemplified by the one-step synthesis of the ipecacuanha
alkaloid emitine 5d and iso-emitine 5e (5d/5e, 1:1) in 76%
Scheme 1. Reagents and conditions: (a) (i) CH2(CO2Me)2, cat. ent-
7 (10 mol-%), EtOH, room temp. (ii) 3, TFA (1 equiv.), CH2Cl2,
50 °C. (b) LiAlH4, THF, reflux. (c) (COCl)2 (2 equiv.), DMSO,
CH2Cl2, TEA, –78 °C. (d) (COCl)2 (0.95 equiv.), DMSO, CH2Cl2,
TEA, –78 °C. (e) Ph3PMeBr, BuLi, THF. (f) (i) H2 (95–115 psi),
Pd/C, MeOH. (ii) 3 n HCl, H2 (95–115 psi), Pd/C, MeOH.
the diastereoisomers 24 in 60% combined yield, and 24bb
in 26% yield with 97% ee. To install the same relative
stereochemistry as that of alkaloid 5a, the crude dia-
stereomeric mixture containing α-isomer 24aЈ was epimer-
ized using lithium diisopropylamide (LDA) to give 24a in
41% yield (two steps from 13a) with more than 20:1 dr and
92% ee. The other diastereoisomers (24b, 24aЈ, and 24bЈ)
were isolated in 16% yield with a respective ratio of
55:28:17. Subsequent, reduction of 24a with LiAlH4 gave
the corresponding alcohol 25a in 49% yield. The direct re-
duction of the crude diastereomeric mixture of 24aЈ and
24b (3:1) and 24bb gave the corresponding alcohol 25aЈ in
40% yield (two steps from 13a) with more than 20:1 dr and
92% ee. Alcohol 25a was more resistant to the Swern condi-
tions as compared to alcohol 17, and we were therefore able
Scheme 2. Reagents and conditions: (a) (i) CH2(CO2Me)2, cat. ent-
7 (10 mol-%), EtOH, room temp. (ii) 2b, HCl (4 n, dioxane),
CH2Cl2, room temp. (b) LDA, THF, –78 °C. (c) LiAlH4, THF, re-
flux. (d) (i) (COCl)2, DMSO, CH2Cl2, TEA, –78 °C. (ii) Ph3PMeBr,
BuLi, THF. (e) (i) H2 (95–115 psi), Pd/C, MeOH. (ii) 3 n HCl, H2
to perform a one-pot tandem oxidation/Wittig sequence to (95–115 psi), Pd/C, MeOH.
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A. Córdova et al.
FULL PAPER
combined yield (Scheme 3). In addition, emitine 5d can also pot reactions: a tandem Swern oxidation/Wittig and a tan-
be prepared stereoselectively in two steps from protometine dem hydrogenation sequence. The concept of biomimetic
5c using Tietze’s procedures.[21]
synthetic divergent assembly of secologanine natural prod-
ucts was demonstrated by the expeditious total syntheses
of (–)-dihydrocorynanthenol (five steps), (–)-protoemetinol
(more than 99% ee; four steps), (–)-protoemetine (more
than 99% ee; five steps), (–)-3-epi-protoemetinol (three
steps), and the total synthesis of emetine (six steps). Studies
towards the total synthesis of other natural products, diver-
sity oriented synthesis, and generation of natural-product-
like libraries using the disclosed divergent catalytic asym-
metric multicomponent approach are ongoing in our
laboratories.
Experimental Section
General Methods: Chemicals and solvents were either purchased as
puriss P. A. grade from commercial suppliers or purified by stan-
dards techniques. For thin-layer chromatography (TLC), silica gel
plates Merck 60 F254 were used; compounds were visualized by
irradiation with UV light and/or by treatment with a solution of
ammonium molybdate (100 g), Ce(SO4)2 (2 g), and 10% H2SO4
(1 L) followed by heating, or by treatment with a solution of potas-
sium permanganate (3 g), K2CO3 (20 g), 5% aq. NaOH (5 mL) and
water (300 mL) followed by heating. Flash chromatography was
performed using silica gel Merck 60 (particle size 0.040–0.063 mm).
1H and 13C NMR spectra were recorded with a Bruker AM400
spectrometer. Chemical shifts are given in δ units (ppm) relative to
tetramethylsilane (TMS); coupling constants (J) are given in Hz.
The spectra were recorded in CDCl3 as solvent at room tempera-
ture; CDCl3 served as internal standard (δ = 7.26 ppm for 1H NMR
and δ = 77.16 ppm for 13C NMR). Peaks are labeled as: singlet (s),
doublet (d), triplet (t), quartet (q), and multiplet (m). HPLC was
carried out with a Waters 2690 Millenium fitted with a photodiode
array detector. Optical rotations were recorded with a Perkin–
Elmer 241 Polarimeter (d = 589 nm, 1 dm cell). High-resolution
mass spectra (ESI) were obtained with a Bruker MicroTOF spec-
trometer.
Scheme 3. Reagents and conditions: (a) (COCl)2, DMSO, CH2Cl2,
TEA, –78 °C. (b) 2b, HCl (4N, dioxane), CH2Cl2, room temp.
Total Synthesis of (–)-3-epi-Protoemetinol (5b)
After completing the total synthesis of secologanine
dopamine alkaloids 5a and 5c, we finalized the asymmetric
synthesis of (–)-3-epi-protoemetinol (5b; Scheme 4). Thus,
performing the one-pot tandem Swern oxidation/Wittig re-
action on alcohol 25aЈ gave olefin 26aЈ in 62% yield. Subse-
quent one-pot hydrogenation completed the total synthesis
of 3-epi-protoemetinol (5b) in 75% yield.
Typical Experimental Procedure for the Catalytic Asymmetric One-
Pot, Three-Component Reaction Between 13a, 3, and Malonate: To
a pressure tube containing a solution of enal 13a (190 mg,
1.0 mmol) in EtOH (2.0 mL), was added catalyst ent-7 (32 mg,
0.1 mmol). After stirring for 2 min, dimethyl malonate (0.34 mL,
3 mmol) was added. The reaction was stirred at room temperature
for 64 h to reach full conversion. The solvent was removed under
reduced pressure and CH2Cl2 (100 mL), tryptamine 3 (240 mg,
1.5 mmol), and trifluoroacetic acid (76 μL, 1.0 mmol) were sequen-
tially added and the sealed tube was heated in an oil bath at 50 °C.
After 16 h, the temperature was decreased to room temperature
and the reaction mixture was poured into saturated aqueous
NaHCO3 solution (60 mL). The phases were separated and the
aqueous layer was extracted with CH2Cl2 (2ϫ 30 mL). The organic
phases were combined, dried with anhydrous Na2SO4, filtered and
concentrated. The residue was separated with flash chromatog-
raphy on silica gel (pentane/EtOAc, 2:1 to 2:3) to furnish the prod-
uct 16a (204 mg, 47% yield). The other diastereoisomers 16 were
also isolated as a mixture of three diastereomers (78 mg, 18% yield;
16b/16aЈ/16bЈ = 67:26:7). The flash system was then changed to
EtOAc/MeOH, 10:1 and 17 (Rf = 0.34; EtOAc/MeOH, 10:1) was
isolated (84 mg, 18% yield). Heating 17 in CH2Cl2 (20 mL) using
a sealed pressure tube gave another crop of product 16b and 16bЈ
Scheme 4. Reagents and conditions: (a) (i) (COCl)2, DMSO,
CH2Cl2, TEA, –78 °C. (ii) Ph3PMeBr, BuLi, THF. (b) (i) H2 (95–
115 psi), Pd/C, MeOH. (ii) 3 n HCl, H2 (95–115 psi), Pd/C, MeOH.
Conclusions
We have developed a divergent strategy for the concise
total synthesis of secologanine, dopamine, and tryptamine
alkaloids through a one-pot, three-component catalytic
asymmetric Michael/Pictet–Spengler/lactamization cascade
reaction. The total syntheses also included two further one- (16b/16bЈ = 84:16, 100 mg).
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Synthesis of Secologanine Tryptamine and Dopamine Alkaloids
Methyl (2R,3R,12bS)-2-[2-(Benzyloxy)ethyl]-4-oxo-1,2,3,4,6,7,12,
12b-octahydroindolo[2,3-a]quinolizine-3-carboxylate (16a): Rf = 0.32
(pentane/EtOAc, 1:1); H NMR: δ = 8.33 (br., 1 H), 7.50 (d, J =
sphere, a solution of compound 16a (392 mg, 0.91 mmol) in dry
THF (50 mL) was cooled to 0 °C with an ice-bath. LiAlH4
(138 mg, 3.6 mmol) was added portionwise (over 20 min) to this
1
7.6 Hz, 1 H), 7.38–7.30 (m, 6 H), 7.22–7.18 (m, 1 H), 7.15–7.11 (m, vigorously stirred solution. The reaction was stirred at this tem-
1 H), 5.15–5.10 (m, 1 H), 4.78 (dd, J = 11.2, 3.2 Hz, 1 H), 4.54 (d, perature for 30 min and then heated to reflux for 15 h. After
J = 12.0 Hz, 1 H), 4.45 (d, J = 12.0 Hz, 1 H), 3.73 (s, 3 H), 3.63–
decreasing the temperature to 0 °C with an ice-bath, the reaction
3.57 (m, 2 H), 3.21 (d, J = 11.6 Hz, 1 H), 2.93–2.75 (m, 3 H), 2.60– was carefully quenched with the addition of a small amount of
2.51 (m, 2 H), 1.83–1.77 (m, 1 H), 1.57–1.50 (m, 1 H), 1.40 (q, J water (added dropwise). The mixture was dried with anhydrous
= 12.4 Hz, 1 H) ppm. 13C NMR: δ = 171.2, 165.4, 138.4, 136.4,
132.8, 128.5, 127.9, 127.8, 126.7, 122.2, 119.8, 118.4, 111.1, 108.9,
72. 8, 66.9, 56.5, 53.7, 52.5, 40.3, 33.8, 33.3, 32.3, 21.0 ppm. HRMS
(ESI): calcd. for C26H28N2O4Na [M + Na]+ 455.1941; found
455.1945. [α]2D5 = –53.9 (c = 1.0, CHCl3) for an enantiomerically
enriched sample of 92% ee. The enantiomeric excess was deter-
mined by HPLC analysis in comparison with authentic racemic
material (AD column; i-hexane/i-PrOH, 70:30; 0.5 mL/min;
222 nm); tr = 22.9 (minor enantiomer), 40.2 (major enantio-
mer) min.
Na2SO4, filtered, concentrated, and purified by silica gel column
chromatography (EtOAc/MeOH, 15:1 to 8:1) to furnish the alcohol
product 18a (248 mg, 70% yield). Rf = 0.24 (EtOAc/MeOH, 10:1);
1H NMR: δ = 7.55 (br., 1 H), 7.47 (d, J = 6.4 Hz, 1 H), 7.42–7.35
(m, 5 H), 7.29 (d, J = 6.4 Hz, 1 H), 7.15–7.12 (m, 1 H), 7.10–7.07
(m, 1 H), 4.61 (d, J = 9.6 Hz, 1 H), 4.47 (d, J = 9.6 Hz, 1 H), 3.74–
3.67 (m, 2 H), 3.63–3.55 (m, 2 H), 3.20–3.09 (m, 3 H), 3.03–2.96
(m, 1 H), 2.74–2.71 (m, 1 H), 2.61 (td, J = 9.0, 3.5 Hz, 1 H), 2.37
(t, J = 8.8 Hz, 1 H), 2.07–2.01 (m, 2 H), 1.72 (br., 3 H), 1.47–1.41
(m, 1 H), 1.32 (q, J = 9.5 Hz, 1 H) ppm. 13C NMR: δ = 138.5,
136.1, 134.8, 128.7, 128.3, 128.0, 127.6, 121.5, 119.6, 118.3, 110.8,
108.3, 73.2, 67.8, 63.4, 59.8, 59.1, 53.2, 43.7, 35.5, 34.2, 32.8,
21.8 ppm. HRMS (ESI): calcd. for C25H31N2O2 [M + H]+
391.2380; found 391.2389. [α]2D5 = 4.9 (c = 1.0, MeOH).
Methyl (2R,3S,12bS)-2-[2-(Benzyloxy)ethyl]-4-oxo-1,2,3,4,6,7,12,
12b-octahydroindolo[2,3-a]quinolizine-3-carboxylate (16aЈ): Rf
=
1
0.17 (pentane/EtOAc, 1:1); H NMR: δ = 7.59 (br., 1 H), 7.50 (d,
J = 6.0 Hz, 1 H), 7.42–7.31 (m, 6 H), 7.21–7.17 (m, 1 H), 7.14–
7.11 (m, 1 H), 5.18–5.12 (m, 1 H), 4.74 (dd, J = 8.8, 4.0 Hz, 1 H),
4.58 (d, J = 9.6 Hz, 1 H), 4.49 (d, J = 9.6 Hz, 1 H), 3.68–3.60 (m,
6 H), 2.90–2.86 (m, 2 H), 2.82–2.77 (m, 1 H), 2.46–2.44 (m, 1 H),
2.18–2.07 (m, 2 H), 1.79–1.74 (m, 1 H), 1.62–1.57 (m, 1 H) ppm.
13C NMR: δ = 170.0, 165.0, 138.5, 136.4, 132.8, 128.7, 128.2, 128.0,
127.0, 122.4, 120.1, 118.6, 111.0, 109.7, 73.2, 67.0, 54.2, 52.7, 52.4,
40.6, 32.4, 31.0, 30.3, 21.1 ppm. HRMS (ESI): calcd. for
C26H28N2O4Na [M + Na]+ 455.1941; found 455.1943. The relative
configuration of compound 16aЈ was determined by an epimeri-
zation experiment with LDA (16a/16aЈ = 4:1).
(2R,3R,12bS)-2-[2-(Benzyloxy)ethyl]-1,2,3,4,6,7,12,12b-octahydro-
indolo[2,3-a]quinolizine-3-carbaldehyde (20): Under an N2 atmo-
sphere, to a Schlenk tube containing a solution of oxalyl chloride
(12 μL, 0.142 mmol) in dry CH2Cl2 (1 mL), was added dropwise a
solution of DMSO (21 μL, 0.297 mmol) in CH2Cl2 (1 mL) at
–78 °C. After stirring for 10 min, a solution of compound 18a
(58 mg, 0.148 mmol) in DMSO/CH2Cl2 (2.2 mL, 1:10) was added
dropwise over 5 min. The reaction was stirred for 30 min. Next,
Et3N (104 μL, 0.743 mmol) was added dropwise and the mixture
was stirred for 15 min. The cold bath was removed and the reaction
mixture was stirred for an additional 10 min. Water (2 mL) was
added to quench the reaction, the phases were separated, and the
aqueous phase was extracted with CH2Cl2 (2ϫ 2 mL each). The
Methyl (2R,3S,12bR)-2-[2-(Benzyloxy)ethyl]-4-oxo-1,2,3,4,6,7,12,
12b-octahydroindolo[2,3-a]quinolizine-3-carboxylate (16bЈ): Rf
=
0.17 (pentane/EtOAc, 1:1); 1H NMR: δ = 7.48–7.45 (m, 2 H), 7.39–
7.33 (m, 5 H), 7.17–7.09 (m, 3 H), 5.07–5.00 (m, 1 H), 4.97 (br., 1 organic phases were combined, dried with anhydrous Na2SO4, fil-
H), 4.48 (q, J = 9.7 Hz, 2 H), 3.74 (s, 3 H), 3.68–3.63 (m, 1 H),
3.55–3.50 (m, 2 H), 3.00–2.92 (m, 2 H), 2.73–2.67 (m, 1 H), 2.58–
2.52 (m, 1 H), 2.25–2.20 (m, 1 H), 2.16–2.13 (m, 1 H), 1.83–1.77
tered, and concentrated. The residue was separated by flash
chromatography on silica gel (pentane/EtOAc, 1:1) to give com-
pound 20 (48 mg, 87% yield). The flash system was changed to
(m, 1 H), 1.75–1.67 (m, 1 H) ppm. 13C NMR: δ = 170.1, 165.4, EtOAc/MeOH (8:1) and 5 mg of excess compound 18a could be
1
138.4, 136.1, 133.2, 128.8, 128.1, 127.9, 127.4, 122.3, 120.0, 118.4,
111.2, 110.8, 73.3, 68.6, 53.5, 53.1, 52.4, 42.5, 31.12, 31.08, 29.0,
21.0 ppm. HRMS (ESI): calcd. for C26H28N2O4Na [M + Na]+
455.1941; found 455.1939.
recovered. Rf = 0.30 (pentane/EtOAc, 1:1); H NMR: δ = 9.73 (d,
J = 2.8 Hz, 1 H), 7.55 (br., 1 H), 7.47 (d, J = 7.6 Hz, 1 H), 7.42–
7.36 (m, 5 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.16 (td, J = 7.1, 1.2 Hz,
1 H), 7.12–7.08 (m, 1 H), 4.60 (d, J = 12.0 Hz, 1 H), 4.45 (d, J =
12.0 Hz, 1 H), 3.61–3.57 (m, 2 H), 3.23 (dd, J = 11.4, 1.7 Hz, 1 H),
3.15 (dd, J = 11.3, 4.1 Hz, 1 H), 3.12–3.08 (m, 1 H), 3.02–2.94 (m,
1 H), 2.77–2.72 (m, 1 H), 2.68–2.57 (m, 2 H), 2.43 (t, J = 11.2 Hz,
1 H), 2.17–2.09 (m, 2 H), 1.97–1.92 (m, 1 H), 1.53–1.47 (m, 1 H),
1.29 (q, J = 11.7 Hz, 1 H) ppm. 13C NMR: δ = 203.2, 138.5, 136.1,
134.2, 128.6, 128.2, 127.9, 127.3, 121.5, 119.5, 118.3, 110.8, 108.1,
72.8, 66.9, 59.0, 54.6, 54.4, 52.8, 34.3, 33.7, 33.0, 21.7 ppm. HRMS
(ESI): calcd. for C25H29N2O2 [M + H]+ 389.2224; found 389.2231.
[α]2D5 = –22.5 (c = 1.0, CHCl3).
Methyl (2R,3R,12bR)-2-[2-(Benzyloxy)ethyl]-4-oxo-1,2,3,4,6,7,12,
12b-octahydroindolo[2,3-a]quinolizine-3-carboxylate (16b): Rf = 0.15
(pentane/EtOAc, 1:1); 1H NMR: δ = 7.47 (d, J = 6.0 Hz, 1 H),
7.43–7.36 (m, 6 H), 7.17–7.15 (m, 2 H), 7.13–7.09 (m, 1 H), 5.09–
5.05 (m, 1 H), 4.87–4.84 (m, 1 H), 4.55 (d, J = 9.2 Hz, 1 H), 4.50
(d, J = 9.2 Hz, 1 H), 3.71–3.69 (m, 1 H), 3.68 (s, 3 H), 3.61–3.57
(m, 1 H), 3.35 (d, J = 4.4 Hz, 1 H), 2.95–2.89 (m, 2 H), 2.75–2.72
(m, 1 H), 2.47–2.24 (m, 1 H), 2.20–2.16 (m, 1 H), 1.80–1.75 (m, 2
H) ppm. 13C NMR: δ = 170.8, 165.3, 138.3, 136.2, 132.8, 128.7,
128.0, 127.9, 127.1, 122.1, 119.8, 118.3, 111.2, 109.9, 73.2, 68.3,
54.8, 52.6, 51.7, 41.4, 32.5, 31.6, 30.1, 21.0 ppm. HRMS (ESI):
calcd. for C26H28N2O4Na [M + Na]+ 455.1941; found 455.1946.
[α]2D5 = 25.0 (c = 1.0, CHCl3) for an enantiomerically enriched sam-
ple of 95% ee. The enantiomeric excess was determined by HPLC
analysis in comparison with authentic racemic material (AD col-
umn; i-hexane/i-PrOH, 70:30; 0.5 mL/min; 222 nm); tr = 22.3
(major enantiomer), 29.7 (minor enantiomer) min.
(2R,3R,12bS)-2-[2-(Benzyloxy)ethyl]-3-vinyl-1,2,3,4,6,7,12,12b-octa-
hydroindolo[2,3-a]quinolizine (21): Under an N2 atmosphere, meth-
yltriphenylphosphonium bromide (40 mg, 0.113 mmol) was sus-
pended in dry THF (1 mL) in a Schlenk tube at 0 °C. BuLi (2.5 m
in hexane, 45 μL, 0.113 mmol) was added dropwise. After stirring
for 30 min at this temperature, the mixture was cooled to –78 °C,
compound 20 (22 mg, 0.057 mmol) was added dropwise as a solu-
tion in THF (1 mL). The reaction was continued at the same tem-
perature for 1 h and then at 0 °C for 30 min. Water (1 mL) was
added to quench the reaction and the mixture was extracted with
{(2R,3R,12bS)-2-[2-(Benzyloxy)ethyl]-1,2,3,4,6,7,12,12b-octahydro-
indolo[2,3-a]quinolizin-3-yl}methanol (18a): Under an N2 atmo-
Eur. J. Org. Chem. 2012, 398–408
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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403

A. Córdova et al.
FULL PAPER
CH2Cl2 (3 ϫ 2 mL). The organic extracts were then combined,
dried with anhydrous Na2SO4, filtered, concentrated, and purified
with by chromatography on silica gel (pentane/EtOAc, 2:1) to give
compound 21 (22 mg, Ͼ99% yield). Rf = 0.41 (pentane/EtOAc,
2:1); 1H NMR: δ = 7.54 (br., 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.44–
7.37 (m, 5 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.17–7.13 (m, 1 H), 7.11–
7.03 (m, 1 H), 5.66–5.57 (m, 1 H), 5.15–5.09 (m, 2 H), 4.61 (d, J
= 12.0 Hz, 1 H), 4.46 (d, J = 12.0 Hz, 1 H), 3.58 (dd, J = 7.4,
5.3 Hz, 2 H), 3.19 (dd, J = 11.4, 1.6 Hz, 1 H), 3.10–3.06 (m, 1 H),
3.04–2.94 (m, 2 H), 2.75–2.70 (m, 1 H), 2.63–2.56 (m, 1 H), 2.29
(t, J = 11.0 Hz, 1 H), 2.25–2.20 (m, 1 H), 2.08–2.00 (m, 2 H), 1.61–
1.56 (m, 1 H), 1.35–1.19 (m, 2 H) ppm. 13C NMR: δ = 139.7, 138.9,
136.1, 134.9, 128.6, 128.2, 127.9, 127.5, 121.4, 119.5, 118.3, 116.9,
110.8, 108.2, 72.8, 67.5, 61.4, 59.7, 53.0, 47.6, 37.2, 34.9, 33.3,
21.9 ppm. HRMS (ESI): calcd. for C26H31N2O [M + H]+ 387.2431;
found 387.2426. [α]2D5 = –16.5 (c = 1.0, CHCl3).
J = 9.8 Hz, 1 H), 1.68–1.62 (m, 1 H) ppm. 13C NMR: δ (major
diastereomer) = 203.2, 179.5, 152.7, 140.3, 138.4, 130.3, 128.6,
127.9, 127.8, 127.0, 122.8, 121.7, 73.1, 68.8, 67.2, 58.5, 54.9, 54.3,
50.2, 37.6, 34.0, 32.8, 31.6 ppm. HRMS (ESI): calcd. for
C25H28ClN2O2 [M + H]+ 423.1834; found 423.1827. [α]2D5 = 35 (c
= 0.5, CHCl3).
Typical Experimental Procedure for the Catalytic Asymmetric One-
Pot, Three-Component Reaction Between 13a, 2, and Malonate: To
a round-bottom flask containing a solution of enal 13a (190 mg,
1 mmol) in EtOH (2.0 mL), was added catalyst ent-7 (32 mg,
0.1 mmol). After stirring for 2 min, dimethyl malonate (0.34 mL,
3 mmol) was added and the reaction was stirred at room tempera-
ture for 64 h to reach full conversion. The solvent was removed
under reduced pressure and the residue was dissolved in dry
CH2Cl2 (2 mL). After addition of amide 2b (338 mg, 1.2 mmol),
the solution was cooled with an ice-bath and HCl (4.0 m in dioxane,
2 mL, 8 mmol) was slowly added. After complete addition, the tem-
perature was increased to room temperature and the mixture was
stirred for 90 min and then poured into water (10 mL). To neu-
tralize the acid, excess solid Na2CO3 was carefully added. The re-
sulting mixture was extracted with CH2Cl2 (4ϫ 7 mL). The com-
bined organic extracts were dried with anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. Purification using silica
gel flash chromatography (EtOAc) gave compounds 24 (272 mg,
60% yield) as a mixture of diastereoisomers (24aЈ/24b, 3:1). The
mixture was then dissolved in dry THF (15 mL) and the resulting
solution was cooled to –78 °C under an N2 atmosphere, followed
by dropwise addition of LDA (2.0 m in THF, 0.55 mL, 1.1 mmol).
After stirring this mixture for 3 h at this temperature, the dry ice-
acetone bath was replaced with an ice-bath. Water (5 mL) was
added to the reaction solution and stirring was continued for
30 min. The mixture was extracted with CH2Cl2 (4ϫ 10 mL) and
the extracts were combined, dried with anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. Purification by flash
chromatography using silica gel (pentane/EtOAc: 2:3 to 1:4) af-
forded pure compound 24a (188 mg, 41% yield based on enal 13a)
and a mixture of the other diastereomers of 24 (72 mg, 16% yield
from enal 13a).
(–)-Dihydrocorynanthenol (4a): Compound 21 (18 mg, 0.047 mmol)
was stirred in MeOH (1 mL) under H2 pressure (115 to 95 psi) with
Pd/C (10%; 1 mg) overnight (ca. 16 h). HCl (3 m in water, 31 μL,
0.093 mmol) was added and, after stirring for 2 min, Pd/C (10%;
1 mg) was added and the reaction was continued for 24 h under H2
pressure (115 to 95 psi). The mixture was then filtered through Ce-
lite and concentrated on a rotavapor to remove MeOH. The residue
was dispersed in saturated aqueous NaHCO3 (5 mL) and CH2Cl2
(2 mL). The phases were separated and the aqueous layers was ex-
tracted with CH2Cl2 (2ϫ 2 mL). The organic phases were com-
bined, dried with anhydrous Na2SO4, filtered, and concentrated.
The residue was purified with flash chromatography on silica gel
(EtOAc/MeOH, 10:1) to furnish the final product 4a (12 mg, 86%
1
yield). Rf = 0.29 (EtOAc/MeOH, 10:1); H NMR: δ = 8.20 (br., 1
H), 7.46 (d, J = 7.2 Hz, 1 H), 7.30 (d, J = 7.6 Hz, 1 H), 7.15–7.06
(m, 2 H), 3.75–3.71 (m, 2 H), 3.15–2.97 (m, 4 H), 2.90 (br., 1 H),
2.72 (d, J = 15.0, 4.2 Hz, 1 H), 2.56 (td, J = 11.0, 4.4 Hz, 1 H),
2.22 (d, J = 12.4 Hz, 1 H), 2.06–1.92 (m, 2 H), 1.69–1.60 (m, 1 H),
1.49–1.24 (m, 4 H), 1.17–1.06 (m, 1 H), 0.90 (t, J = 7.4 Hz, 3
H) ppm. 13C NMR: δ = 136.3, 134.8, 127.5, 121.5, 119.5, 118.3,
111.0, 108.0, 60.44, 60.41, 59.9, 53.1, 41.7, 37.2, 35.6, 35.4, 23.6,
21.7, 11.1 ppm. HRMS (ESI): calcd. for C19H27N2O [M + H]+
299.2118; found 299.2113. [α]2D5 = –15.1 (c = 1.0, CHCl3).
Methyl (2R,3R,11bS)-2-[2-(Benzyloxy)ethyl]-9,10-dimethoxy-4-oxo-
2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline-3-carboxylate
(2R,3R,12bS)-2-[2-(Benzyloxy)ethyl]-7a-chloro-1,2,3,4,6,7,7a,12b-
octahydroindolo[2,3-a]quinolizine-3-carbaldehyde (19): Under an N2
atmosphere, to a Schlenk tube containing a solution of oxalyl
chloride (8 μL, 0.092 mmol) in dry CH2Cl2 (0.5 mL) at –78 °C, was
added dropwise a solution of DMSO (14 μL, 0.184 mmol) in
CH2Cl2 (0.5 mL). After stirring for 10 min, a solution of com-
pound 18a (18 mg, 0.046 mmol) in DMSO/CH2Cl2 (1.1 mL, 1:10)
was added dropwise over 5 min. The reaction was stirred for
30 min, then Et3N (64 μL, 0.46 mmol) was added dropwise. The
mixture was stirred for 15 min then the cold bath was removed and
the stirring was continued for a further 10 min. Water (2 mL) was
added to quench the reaction. The phases were separated and the
aqueous phase was extracted with CH2Cl2 (2ϫ 2 mL). The organic
phases were combined, dried with anhydrous Na2SO4, filtered, and
concentrated. The residue was separated with flash chromatog-
raphy on silica gel (pentane/EtOAc, 1:1) to give compound 19 (dr
ca. 8:1, 15 mg, 77% yield). Rf = 0.22 (pentane/EtOAc, 1:1); 1H
NMR: δ (major diastereomer) = 9.73 (d, J = 2.0 Hz, 1 H), 7.64 (d,
J = 6.2 Hz, 1 H), 7.50–7.48 (m, 1 H), 7.43–7.39 (m, 1 H), 7.34–
7.27 (m, 6 H), 4.49 (dd, J = 17.5, 9.5 Hz, 2 H), 3.61 (dd, J = 5.6,
1
(24a): Rf = 0.60 (EtOAc); H NMR: δ = 7.35–7.31 (m, 4 H), 7.30–
7.27 (m, 1 H), 6.60 (s, 1 H), 6.55 (s, 1 H), 4.84–4.79 (m, 1 H), 4.67
(dd, J = 11.2, 4.0 Hz, 1 H), 4.54 (d, J = 11.6 Hz, 1 H), 4.46 (d, J
= 11.6 Hz, 1 H), 3.86 (s, 3 H), 3.78 (s, 3 H), 3.77 (s, 3 H), 3.65–
3.57 (m, 2 H), 3.19 (d, J = 11.2 Hz, 1 H), 2.90–2.80 (m, 2 H), 2.67–
2.51 (m, 3 H), 1.82–1.74 (m, 1 H), 1.64–1.58 (m, 1 H), 1.39 (q, J
= 12.4 Hz, 1 H) ppm. 13C NMR: δ = 171.4, 165.4, 148.1, 148.0,
138.4, 128.57, 128.53, 127.85, 127.76, 127.11, 111.6, 108.4, 73.1,
67.6, 56.3, 56.2, 56.1, 52.6, 40.0, 36.1, 34.3, 32.9, 28.5 ppm. HRMS
(ESI): calcd. for C26H31NO6Na [M + Na]+ 476.2044; found
476.2046. [α]2D5 = –15.1 (c = 1.0, CHCl3) for an enantiomerically
enriched sample of 92% ee. The enantiomeric excess was deter-
mined by HPLC analysis in comparison with authentic racemic
material (AS column; i-hexane/i-PrOH, 70:30; 0.5 mL/min;
210 nm): tr = 37.4 (minor enantiomer), 49.9 (major enantiomer)
min.
{(2R,3R,11bS)-2-[2-(Benzyloxy)ethyl]-9,10-dimethoxy-2,3,4,6,
7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-3-yl}methanol (25a):
4.4 Hz, 2 H), 3.35 (dd, J = 8.8, 1.7 Hz, 1 H), 3.10–3.08 (m, 1 H), Compound 24a (421 mg, 0.93 mmol) was dissolved in dry THF
2.95–2.90 (m, 1 H), 2.84–2.81 (m, 1 H), 2.58 (dt, J = 11.6, 1.9 Hz, (10 mL) and cooled to 0 °C with an ice-bath. To this vigorously
1 H), 2.51–2.43 (m, 2 H), 2.35 (dt, J = 10.8, 1.3 Hz, 1 H), 2.13– stirred solution, LiAlH4 (141 mg, 3.72 mmol) was added carefully
2.06 (m, 1 H), 1.97–1.90 (m, 1 H), 1.86–1.80 (m, 1 H), 1.73 (q, at this temperature. After stirring for an additional 30 min at this
404
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Eur. J. Org. Chem. 2012, 398–408

Synthesis of Secologanine Tryptamine and Dopamine Alkaloids
temperature the resulting reaction mixture was heated to reflux for
16 h. After decreasing the temperature again to 0 °C with an ice-
bath, the reaction was carefully quenched with a small amount of
water (added dropwise). The mixture was dried with anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (EtOAc/
MeOH, 10:1 to 6:1) to give the corresponding alcohol product 25a
(188 mg, 49% yield). Rf = 0.25 (EtOAc/MeOH, 3:1); 1H NMR (400
MHz, CDCl3): δ = 7.35–7.33 (m, 4 H), 7.30–7.28 (m, 1 H), 6.63 (s,
95 psi) for 20 h. HCl (3 m in water, 93 μL, 0.3 mmol) was added
and, after stirring for 2 min, Pd/C (10%; 3 mg) was added. The
reaction was continued for 16 h under H2 pressure (115 to 95 psi).
The mixture was then filtered through Celite and concentrated on a
rotavapor to remove MeOH. The residue was dispersed in saturated
aqueous NaHCO3 (10 mL) and CH2Cl2 (5 mL). The phases were
separated and the aqueous layer was extracted with CH2Cl2 (2ϫ
5 mL). The organic phases were combined, dried with anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
1 H), 6.57 (s, 1 H), 4.54 (dd, J = 14.8, 9.6 Hz, 2 H), 3.84 (s, 3 H), residue was purified by flash chromatography on silica gel (EtOAc/
3.81 (s, 3 H), 3.73–3.67 (m, 2 H), 3.62–3.58 (m, 2 H), 3.07 (d, J =
MeOH, 3;1) to furnish the final product 5a (16 mg, 72% yield). Rf
9.2 Hz, 3 H), 2.99–2.96 (m, 1 H), 2.64–2.61 (m, 1 H), 2.52–2.47 (m, = 0.29 (EtOAc/MeOH, 3:1); 1H NMR (400 MHz, CDCl3): δ = 6.68
1 H), 2.32–2.28 (m, 2 H), 2.08 (s, 1 H), 2.02–1.95 (m, 1 H), 1.69– (s, 1 H), 6.57 (s, 1 H), 3.85 (s, 3 H), 3.84 (s, 3 H), 3.82–3.75 (m, 2
1.67 (m, 2 H), 1.56–1.51 (m, 1 H), 1.27 (q, J = 9.5 Hz, 1 H) ppm.
H), 3.08 (d, J = 8.8 Hz, 3 H), 3.01–2.98 (m, 1 H), 2.63 (d, J =
13C NMR (100 MHz, CDCl3): δ = 147.6, 147.2, 138.2, 129.9, 128.6, 12.4 Hz, 1 H), 2.52–2.47 (m, 1 H), 2.34 (d, J = 10.4 Hz, 1 H), 2.07
127.9, 127.8, 126.8, 111.6, 108.4, 73.3, 68.5, 63.4, 62.6, 59.9, 56.2,
55.9, 52.4, 43.0, 37.5, 34.9, 33.0, 29.2 ppm. HRMS (ESI): calcd. for
C25H33NO4 [M + H]+ 412.2482; found 412.2484. [α]2D5 = –7.9 (c =
1.0, CHCl3).
(t, J = 8 Hz, 1 H), 1.98–1.93 (m, 1 H), 1.72–1.65 (m, 1 H), 1.46 (d,
J = 4.4 Hz, 3 H), 1.16 (s, 1 H), 1.15–1.11 (m, 1 H), 0.92 (t, J =
6.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 147.7, 147.4,
129.9, 126.8, 111.7, 108.5, 62.8, 61.5, 60.8, 56.3, 56.0, 52.5, 41.3,
37.7, 37.3, 36.1, 29.2, 23.6, 11.2 ppm. HRMS (ESI): calcd. for
C26H33NO3 [M + H]+ 320.2220; found 320.2227. [α]2D5 = –47.4 (c =
0.5, CHCl3).
(2R,3R,11bS)-2-[2-(Benzyloxy)ethyl]-9,10-dimethoxy-3-vinyl-
2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline (26a): Under
an N2 atmosphere, to a solution of oxalyl chloride (46 μL,
0.55 mmol) in dry CH2Cl2 (0.5 mL) in a three-neck flask at –78 °C,
was added dropwise a solution of DMSO (85 μL, 1.1 mmol) in
CH2Cl2 (0.5 mL). After stirring for 10 min, a solution of 25a
2-[(2R,3R,11bS)-3-Ethyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-
1H-pyrido[2,1-a]isoquinolin-2-yl]ethyl Acetate: To a solution of pro-
tometinol 5a (5 mg, 0.016 mmol) in CH2Cl2 (1 mL), was sequen-
(188 mg, 0.46 mmol) in CH2Cl2 (4 mL) was added dropwise. The tially added DMAP (1 mg), Et3N (7 μL, 0.05 mmol), and Ac2O
reaction was stirred for 30 min and then Et3N (0.32 mL, 2.3 mmol)
was added dropwise. After complete addition at –78 °C, stirring
was prolonged for a further 15 min at this temperature. The tem-
perature was increased to room temperature and, after 10 min stir-
ring, water (2 mL) was added to quench the reaction. The phases
were separated and the aqueous phase was extracted with CH2Cl2
(2ϫ 5 mL). The organic layers were combined, dried with anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure
to give the crude aldehyde product. This crude product was then
dissolved in dry THF (4 mL). Under an N2 atmosphere, methyltri-
phenylphosphonium bromide (326 mg, 0.91 mmol) was suspended
in dry THF (3 mL) in a Schlenk tube at 0 °C and BuLi (2.5 m in
hexane, 0.37 mL, 0.91 mmol) was added dropwise. After stirring
for 30 min at this temperature, the mixture was cooled to –78 °C,
the above solution of the crude aldehyde was added dropwise. The
reaction was continued at the same temperature for 1 h and then
at 0 °C for 30 min. Water (2 mL) was added to quench the reaction
and the mixture was extracted with CH2Cl2 (3ϫ 10 mL). The or-
ganic extracts were combined, dried with anhydrous Na2SO4, fil-
tered, concentrated, and purified by flash chromatography on silica
gel (EtOAc) to give compound 26a (133 mg, 71% yield). Rf = 0.37
(EtOAc); 1H NMR (400 MHz, CDCl3): δ = 7.36–7.32 (m, 4 H),
7.29–7.26 (m, 1 H), 6.62 (s, 1 H), 6.57 (s, 1 H), 5.62–5.56 (m, 1 H),
5.14–5.07 (m, 2 H), 4.52 (dd, J = 14.8, 9.6 Hz, 2 H), 3.84 (s, 3 H),
3.78 (s, 3 H), 3.59–3.57 (m, 2 H), 3.1 (d, J = 10.4 Hz, 2 H), 2.95–
2.90 (m, 1 H), 2.90 (dd, J = 6.0, 2.8 Hz, 1 H), 2.62 (d, J = 12.8 Hz,
1 H), 2.51–2.48 (m, 1 H), 2.35 (dt, J = 5.4, 2.6 Hz, 1 H), 2.24 (t, J
= 8.9 Hz, 1 H), 2.20–2.14 (m, 1 H), 2.02–1.96 (m, 1 H), 1.61–1.55
(m, 1 H), 1.44–1.37 (m, 1 H), 1.19 (q, J = 9.7 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 147.6, 147.3, 140.0, 138.8, 130.2,
128.5, 127.7, 127.7, 126.9, 116.8, 111.6, 108.5, 72.9, 68.2, 62.6, 62.3,
56.3, 56.0, 52.2, 46.9, 38.0, 36.9, 33.7, 29.8, 29.3 ppm. HRMS
(ESI): calcd. for C26H33NO3 [M + H]+ 408.2533; found 408.2526.
[α]2D5 = –2.96 (c = 1.0, CHCl3).
(3 μL, 0.031 mmol). After 16 h stirring at room temperature, the
reaction mixture was directly loaded on a silica gel column and
purified by chromatography (EtOAc) to give the corresponding
acetylated product (5 mg, 88 % yield). Rf = 0.20 (EtOAc); 1H
NMR: δ = 6.67 (s, 1 H), 6.57 (s, 1 H), 4.19 (dd, J = 7.5, 6.4 Hz, 2
H), 3.86 (s, 3 H), 3.84 (s, 3 H), 3.15–3.06 (m, 3 H), 3.01–2.96 (m,
1 H), 2.63 (d, J = 15.1 Hz, 1 H), 2.48 (td, J = 11.4, 4.0 Hz, 1 H),
2.32 (dt, J = 12.7, 3.0 Hz, 1 H), 2.06 (s, 3 H), 2.04–2.00 (m, 2 H),
1.72–1.62 (m, 1 H), 1.54–1.38 (m, 3 H), 1.29–1.21 (m, 1 H), 1.18–
1.03 (m, 1 H), 0.92 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR: δ = 171.3,
147.7, 147.4, 130.0, 126.8, 111.7, 108.4, 62.78, 62.76, 61.4, 56.3,
56.0, 52.5, 41.2, 38.2, 37.3, 31.9, 29.3, 23.6, 21.2, 11.2 ppm. HRMS
(ESI): calcd. for C21H32NO4 [M + H]+ 362.2326; found 362.2316.
[α]2D5 = –5.6 (c = 0.25, CHCl3). The enantiomeric excess was deter-
mined by HPLC analysis in comparison with authentic racemic
material (AD column; i-hexane/i-PrOH, 70:30; 0.5 mL/min;
210.5 nm): tr = 22.8 (major enantiomer) min.
(–)-Protoemetine (5c): Under an N2 atmosphere, to a Schlenk tube
containing a solution of oxalyl chloride (4 μL, 0.045 mmol) in dry
CH2Cl2 (0.5 mL) at –78 °C, was added dropwise a solution of
DMSO (7 μL, 0.09 mmol) in CH2Cl2 (0.5 mL). After stirring for
10 min, a solution of protoemetinol 5a (12 mg, 0.038 mmol) in
CH2Cl2 (1 mL) was added dropwise. The reaction was stirred for
30 min, then Et3N (26 μL, 0.19 mmol) was added dropwise. The
mixture was stirred for 15 min, then the cold bath was removed
and stirring was continued for a further 10 min. Water (2 mL) was
added to quench the reaction, the phases were separated, and the
aqueous phase was extracted with CH2Cl2 (2ϫ 2 mL). The organic
phases were combined, dried with anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (EtOAc/MeOH, 15:1) to furnish
1
protoemetine 5c (9 mg, 75% yield). Rf = 0.13 (EtOAc); H NMR:
δ = 9.87 (dd, J = 1.9, 1.1 Hz, 1 H), 6.63 (s, 1 H), 6.57 (s, 1 H), 3.84
(s, 3 H), 3.83 (s, 3 H), 3.12–3.06 (m, 3 H), 2.98–2.95 (m, 1 H), 2.72
(ddd, J = 12.6, 3.0, 1.0 Hz, 1 H), 2.64–2.60 (m, 1 H), 2.49 (td, J =
9.3, 6.1 Hz, 1 H), 2.36–2.30 (m, 2 H), 2.07 (t, J = 9.0 Hz, 1 H),
1.98–1.90 (m, 1 H), 1.62–1.54 (m, 1 H), 1.51–1.44 (m, 1 H), 1.27
(–)-Protoemetinol (5a): At room temperature, to a solution of com-
pound 26a (56 mg, 0.14 mmol) in MeOH (3 mL), was added Pd/C
(10%; 3 mg), and the mixture was stirred under H2 pressure (115 to
Eur. J. Org. Chem. 2012, 398–408
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
405

A. Córdova et al.
FULL PAPER
(dd, J = 19.3, 9.5 Hz, 1 H), 1.17–1.08 (m, 1 H), 0.93 (t, J = 6.0 Hz,
9.6 Hz, 2 H), 3.96 (d, J = 8.8 Hz, 1 H), 3.88 (dd, J = 8.8, 2.4 Hz,
1 H), 3.82 (s, 3 H), 3.79 (s, 3 H), 3.63–3.55 (m, 3 H), 3.19–3.15 (m,
3 H) ppm. 13C NMR: δ = 202.7, 147.6, 147.3, 129.7, 126.8, 111.6,
108.3, 62.6, 61.3, 56.2, 56.0, 52.6, 48.3, 41.5, 38.4, 36.1, 29.3, 23.9, 2 H), 3.07–3.01 (m, 1 H), 2.96 (q, J = 4.4 Hz, 1 H), 2.68 (d, J =
11.2 ppm. HRMS (ESI): calcd. for C19H28NO3 [M + H]+ 318.2064;
8.8 Hz, 1 H), 2.58 (dd, J = 12.4, 2.0 Hz, 1 H), 2.44 (td, J = 11.8,
3.5 Hz, 1 H), 2.20–2.18 (m, 1 H), 2.07–2.03 (m, 1 H), 1.86–1.78 (m,
2 H), 1.69–1.64 (m, 1 H), 1.61–1.59 (m, 1 H) ppm. 13C NMR: δ =
147.6, 147.4, 138.6, 129.8, 128.5, 127.7, 126.6, 114.4, 108.3, 73.0,
68.0, 64.8, 63.1, 62.3, 56.2, 55.9, 52.8, 37.1, 36.2, 35.5, 33.5,
29.5 ppm. HRMS (ESI): calcd. for C25H34NO4 [M + H]+ 412.2482;
found 412.2487. [α]2D5 = –50.4 (c = 1.0, CHCl3).
found 318.2067. [α]2D5 = –28 (c = 0.1, CHCl3).
Experimental Procedure for the Synthesis of Emetine: To a vial con-
taining a solution of protoemetine 5c (7 mg, 0.022 mmol) in dry
CH2Cl2 (0.1 mL), was added amide 2b (7 mg, 0.026 mmol). The
solution was cooled to 0 °C with an ice-bath, and HCl (4.0 m in
dioxane, 0.1 mL, 0.4 mmol) was slowly added. After complete ad-
dition, the temperature was increased to room temperature and the
mixture was stirred for 90 min, then poured into water (2 mL). Ex-
cess solid Na2CO3 was added carefully to neutralize the acid, and
the resulting mixture was extracted with CH2Cl2 (4ϫ 2 mL). The
combined organic extracts were dried with anhydrous Na2SO4, fil-
tered, concentrated, and purified with flash chromatography on sil-
ica gel (CH2Cl2/MeOH/NH3·H2O, 9:1:0.1) to give a mixture of em-
etine and isoemetine (8 mg, 75% yield, 1:1).
(2R,3S,11bS)-2-[2-(Benzyloxy)ethyl]-9,10-dimethoxy-3-vinyl-
2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline (26aЈ): Under
an N2 atmosphere, to a solution of oxalyl chloride (31 μL,
0.36 mmol) in dry CH2Cl2 (0.5 mL) in a three-neck flask at –78 °C,
was added dropwise a solution of DMSO (56 μL, 0.73 mmol) in
CH2Cl2 (0.5 mL). After stirring for 10 min, a solution of com-
pound 25aЈ (125 mg, 0.3 mmol) in CH2Cl2 (3 mL) was added drop-
wise. The reaction was stirred for 30 min, then Et3N (212 μL,
1.5 mmol) was added dropwise. After complete addition, stirring
was prolonged for 15 min at this temperature and for 10 min at
room temperature. Water (2 mL) was added to quench the reaction,
the phases were separated, and the aqueous phase was extracted
with CH2Cl2 (2ϫ 5 mL). The organic layers were combined, dried
with anhydrous Na2SO4, filtered, and concentrated under reduced
pressure to give the crude aldehyde product (120 mg). This crude
product was then dissolved in dry THF (3 mL).
Emetine and Isoemetine (Mixture): Rf = 0.53 (CH2Cl2/MeOH/
1
NH3·H2O, 9:1:0.5); H NMR: δ = 6.75 (s, 1 H, emetine), 6.73 (s, 1
H, emetine), 6.66 (s, 1 H, isoemetine), 6.59–6.52 (m, 5 H), 4.10 (br.
d, J = 11.0 Hz, 1 H, emetine), 4.06 (t, J = 5.5 Hz, 1 H, isoemetine),
3.87–3.80 (m, 24 H), 3.30–2.95 (m, 12 H), 2.82–2.59 (m, 8 H), 2.53–
2.43 (m, 2 H), 2.37 (br. d, J = 13.0 Hz, 1 H, isoemetine), 2.15–2.01
(m, 3 H), 1.80–1.75 (m, 2 H), 1.67–1.58 (m, 3 H), 1.51–1.41 (m, 3
H), 1.23–1.11 (m, 4 H), 0.95 (t, J = 7.4 Hz, 3 H, isoemetine), 0.90
(t, J = 7.4 Hz, 3 H, emetine) ppm. 13C NMR: δ = 147.7, 147.64,
Under an N2 atmosphere, methyltriphenylphosphonium bromide
147.55, 147.50, 147.47, 147.4, 147.29, 47.27, 132.5, 132.2, 130.4, (217 mg, 0.61 mmol) was suspended in dry THF (2 mL) in a
130.2, 127.2, 127.1, 126.8, 112.2, 112.0, 111.7, 111.6, 109.7, 109.4,
108.8, 108.4, 63.0, 62.6, 61.7, 61.6, 56.4, 56.20, 56.16, 56.1, 56.03,
56.00, 55.98, 55.95, 55.5, 52.7, 52.5, 52.0, 43.7, 43.0, 41.9, 41.3,
Schlenk tube at 0 °C, and BuLi (2.5 m in hexane, 243 μL,
0.61 mmol) was added dropwise. After stirring for 30 min at this
temperature, the mixture was cooled to –78 °C, and the above solu-
40.9, 40.3, 39.6, 37.1, 37.0, 29.8, 29.7, 29.54, 29.45, 24.2, 23.8, 11.5, tion of the crude aldehyde was added dropwise. The reaction was
11.3 ppm. HRMS (ESI): calcd. for C29H41N2O4 [M + H]+
481.3061; found 481.3073.
continued at the same temperature for 1 h and then at 0 °C for
30 min. Water (2 mL) was added to quench the reaction and the
mixture was extracted with CH2Cl2 (3ϫ 7 mL). The organic ex-
tracts were then combined, dried with anhydrous Na2SO4, filtered,
concentrated, and purified with flash chromatography on silica gel
(pentane/EtOAc, 2:1) to give 26aЈ (77 mg, 62% yield). Rf = 0.35
(pentane/EtOAc, 2:1); 1H NMR: δ = 7.39–7.35 (m, 4 H), 7.31–7.28
(m, 1 H), 6.68 (s, 1 H), 6.59 (s, 1 H), 6.24–6.17 (m, 1 H), 5.07 (br.,
1 H), 5.04 (dd, J = 4.8, 1.6 Hz, 1 H), 4.55 (t, J = 10.1 Hz, 2 H),
3.85 (s, 3 H), 3.83 (s, 3 H), 3.61–3.54 (m, 2 H), 3.11–3.06 (m, 2 H),
2.89 (dd, J = 8.9, 1.8 Hz, 1 H), 2.86–2.82 (m, 1 H), 2.59–2.56 (m,
2 H), 2.46–2.41 (m, 1 H), 2.30 (q, J = 2.5 Hz, 1 H), 2.07 (d, J =
10.0 Hz, 1 H), 2.00–1.93 (m, 1 H), 1.66–1.54 (m, 2 H), 1.36 (dd, J
= 19.2, 10.0 Hz, 1 H) ppm. 13C NMR: δ = 147.4, 147.2, §38.9,
138.7, 130.6, 128.4, 127.7, 127.6, 127.2, 115.9, 111.6, 108.3, 72.9,
67.7, 63.3, 62.7, 56.2, 55.9, 52.9, 43.1, 36.1, 34.3, 34.0, 29.4 ppm.
HRMS (ESI): calcd. for C26H34NO3 [M + H]+ 408.2533; found
408.2541. [α]2D5 = –65.4 (c = 1.0, CHCl3).
{(2R,3S,11bS)-2-[2-(Benzyloxy)ethyl]-9,10-dimethoxy-2,3,4,6,7,11b-
hexahydro-1H-pyrido[2,1-a]isoquinolin-3-yl}methanol (25aЈ): To a
flask containing a solution of enal 13a (190 mg, 1 mmol) in EtOH
(2 mL), was added catalyst ent-7 (32 mg, 0.1 mmol). After stirring
for 2 min, dimethyl malonate (0.34 mL, 3 mmol) was added and
the reaction was stirred at room temperature for 64 h to reach full
conversion. The solvent was removed under reduced pressure and
the residue was dissolved in dry CH2Cl2 (2 mL). After addition of
amide 2b (338 mg, 1.2 mmol), the solution was cooled with an ice-
bath and HCl (4.0 m in dioxane, 2 mL, 8 mmol) was slowly added.
After complete addition, the temperature was increased to room
temperature and the mixture was stirred for 90 min and then
poured into water (10 mL). Excess solid Na2CO3 was added care-
fully to neutralize the acid. The resulting mixture was extracted
with CH2Cl2 (4ϫ 7 mL), and the combined organic extracts were
dried with anhydrous Na2SO4, filtered, and concentrated under re-
duced pressure. The residue was dissolved in dry THF (60 mL) and
cooled to 0 °C with an ice-bath. To this solution, LiAlH4 (235 mg,
6 mmol) was added carefully with good stirring. The reaction was
stirred at this temperature for 30 min, and then heated to reflux for
16 h. After cooling to 0 °C with an ice-bath, the reaction was care-
fully quenched by the addition of a small amount of water (added
dropwise). The mixture was dried with anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was sepa-
rated with flash chromatography on silica gel (EtOAc/MeOH, 20:1
to 10:1) to furnish the alcohol product 25aЈ (165 mg, 40% yield).
Rf = 0.29 (EtOAc/MeOH, 10:1); 1H NMR: δ = 7.39–7.32 (m, 4 H),
7.30–7.27 (m, 1 H), 6.61 (s, 1 H), 6.54 (s, 1 H), 4.53 (dd, J = 13.2,
(–)-3-epi-Protometinol (5b): To
a solution of 26aЈ (66 mg,
0.16 mmol) in MeOH (3.2 mL) was added Pd/C (10%; 2 mg) at
room temperature, and the mixture was stirred under H2 pressure
(115 to 95 psi) for 20 h. HCl (3 m in water, 108 μL, 0.32 mmol) was
added and, after stirring for 2 min, Pd/C (10%; 2 mg) was added
and the reaction was continued for 16 h under H2 pressure (115 to
95 psi). The mixture was then filtered through Celite and concen-
trated on a rotavapor to remove MeOH. The residue was dispersed
in saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (5 mL), then
the phases were separated and the aqueous layer was extracted with
CH2Cl2 (2ϫ 5 mL). The organic phases were combined, dried with
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
406
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 398–408

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sure. The residue was purified by flash chromatography on silica
gel (EtOAc/MeOH, 10:1) to furnish the final product 5b (39 mg,
75% yield). Rf = 0.37 (EtOAc/MeOH, 10:1); 1H NMR: δ = 6.69 (s,
1 H), 6.57 (s, 1 H), 3.85 (s, 3 H), 3.84 (s, 3 H), 3.76–3.74 (m, 2 H),
3.10–2.97 (m, 3 H), 2.84 (dd, J = 9.2, 4.8 Hz, 1 H), 2.57 (d, J =
12.4 Hz, 1 H), 2.44 (td, J = 9.3, 3.0 Hz, 1 H), 2.29 (dd, J = 9.2,
2.0 Hz, 1 H), 2.04–2.00 (m, 1 H), 1.94–1.87 (m, 2 H), 1.69–1.55 (m,
3 H), 1.47–1.45 (m, 1 H), 1.35–1.26 (m, 2 H), 0.91 (t, J = 5.8 Hz,
3 H) ppm. 13C NMR: δ = 147.5, 147.2, 130.8, 127.2, 111.7, 108.2,
63.5, 61.0, 59.2, 56.3, 56.0, 53.2, 39.2, 36.8, 36.5, 34.0, 29.5, 17.7,
12.7 ppm. HRMS (ESI): calcd. for C19H30NO3 [M + H]+ 320.2220;
found 320.2217. [α]2D5 = –88.6 (c = 1.0, CHCl3).
[12]
[13]
Supporting Information (see footnote on the first page of this arti-
cle): Complete experimental details, 1H NMR and 13C NMR spec-
tra for all key compounds, HRMS spectra.
Acknowledgments
[14]
The authors gratefully acknowledge the Swedish National Research
Council (VR) and Wenner-Gren-Foundation for financial support.
The Berzelii Center EXSELENT is financially supported by VR
and the Swedish Governmental Agency for Innovation Systems
(VINNOVA).
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Received: September 5, 2011
Published Online: November 16, 2011
408
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