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The Asymmetric Pictet-Spengler Reaction for the
Synthesis of New Enantiopure Tetrahydro-β-Carbolines
Linda Jongbloed (5674905)Bachelorproject
July 2009M. J. Wanner
Prof. H. HiemstraProf. A. M. Brouwer
Synthetic Organic ChemistryVan ‘t Hoff Institute for Molecular Sciences
University of Amsterdam
2
1. Abstract
It was attempted to synthesize new indole alkaloids via the asymmetric Pictet-Spengler
reaction (PS) of Nb-iodoolefin-functionalized tryptamine 9 with aldehyde 10 followed by a
diastereoselective Pd(0)-catalyzed enolate-iodoalkene coupling. However, undesired product
15 was obtained as a racemic mixture. Therefore keto-protected aldehyde 17 was applied in
the PS-reaction and the ee of product 20 was raised to 53%. The deprotection of the acetal
turned out to be difficult and is not accomplished. Due to this the enolate-iodoalkene coupling
is not performed.
2. Samenvatting
Er is een poging gedaan om nieuwe indool alkaloïden te synthetiseren met behulp van de
asymmetrische Pictet-Spengler reactie van aldehyde 10 met Nb-joodolefine-gefunctionaliseerd
tryptamine 9, gevolgd door een enolaat-joodalkeen koppeling gekatalyseerd door Pd(0). Het
ongewenste product 15 was echter verkregen als een racemisch mengsel. Daarom is het
aldehyde 17 met een beschermde keto-groep toegepast in de PS reactie en dit verhoogde de ee
van product 20 naar 53%. De hydrolisatie van de beschermgroep bleek moeilijk te zijn en is
niet voltooid. Hierdoor is de enolaat-joodalkeen koppeling niet uitgevoerd.
Populaire Samenvatting
In dit project is geprobeerd om natuurstoffen te maken waarvan een indoolring een bouwsteen
is. Deze natuurstoffen hebben vaak een specifieke stereochemie en dit kan synthetisch bereikt
worden door toepassing van bepaalde katalysatoren. Voor dit project is de asymmetrische
Pictet-Spengler reactie gebruikt waarbij een tryptamine gekoppeld word aan een aldehyde.
Hierbij is een chirale katalysator gebruikt die de ene enantiomeer van het product in overmaat
kan geven.
3
Table of contents
1. Abstract p. 2
2. Samenvatting en populaire samenvatting p. 2
3. Introduction p. 4
4. Results and Discussion p. 74.1 Synthesis of the functionalized tryptamine p. 74.2 Synthesis of the aldehyde p. 74.3 Pictet-Spengler reaction p. 84.4 Synthesis of the aldehyde with keto-protection group p. 104.5 Pictet-Spengler reaction with aldehyde with protected keto-group p.104.6 Hydrolysis of the acetal p. 11
5. Conclusion and Outlook p. 12
6. Experimental section p. 13
7. Acknowledgement p. 20
8. List of abbreviations p. 20
9. Supplementary p. 219.1 Mechanism of ozonolysis p. 219.2 Mechanism osmiumtetroxide / periodate olefin cleavage p. 219.3 Spectra p. 22
10. References p. 32
4
3. Introduction
Alkaloids of the indole family have been investigated more thoroughly than any other group
of natural alkaloid compounds. This interest stems from the diverse and complex structures of
these products in combination with the wide diversity of important biological activities and
the medicinal application of some of these natural bases1. In figure 1 two examples of
biologically active indole alkaloids are depicted. Reserpine2 1 exhibits a cardiovascular effect
and mitrgynine3 2 exhibits an analgesic effect.
Figure 1: Tetrahydro--carbolines with medicinal effects
A core structural element of indole alkaloids is the tetrahydro--carboline ring. These rings
are generally obtained via the Pictet-Spengler (PS) reaction of tryptamine with an aldehyde in
the presence of a Brønsted acid. This condensation reaction is discovered in 1911 by Amé
Pictet and Theodor Spengler4 and was originally used to synthesize tetrahydro-isoquinolines.
Two decades after the discovery, the Pictet-Spengler reaction was used for the first time to
make tetrahydro--carbolines and since then it has become a standard route for the synthesis
of these compounds.
Scheme 1: mechanism of the Pictet-Spengler reaction
The mechanism of the PS-reaction is shown in scheme 1. The first step is the formation of an
iminiumion by nucleophilic attack of the nitrogen on the aldehyde. Subsequently, the ring is
closed by the attack of C2 on the iminiumion. Then aromaticity is recovered by the loss of the
proton on the C2 position. Most of the natural indole alkaloids have a specific stereochemistry
5
at the C3-position. To introduce this chirality the asymmetric PS-reaction was developed and
this has made the PS reaction an important synthetic method for the synthesis of indole
alkaloids.
Figure 2: Tetrahydro-β-carbolines obtained via organocatalytic asymmetric Pictet-Spengler reaction
Various methods have been invented to obtain enantioselectivity in the PS-reaction. The first
reagent-controlled method was reported by T. Kawate et all5. In this research nitrones were
applied in the presence of chiral boranes as Lewis acids and ee’s up to 90% were achieved. A
drawback of this method is the requirement of excess of chiral borane. In 2004 Taylor and
Jacobsen6 reported a asymmetric PS-reaction with N-acyliminiumions as intermediates (see 3
in figure 2). With chiral thiourea derivatives as catalyst ee’s up to 95% were obtained.
However, the removal of the acyl-group turned out to be difficult. More recently, B. List and
coworkers7 showed an enantioselective PS-reaction with geminal diester functionalized
tryptamines (see 4 in figure 2). As catalyst chiral phosphoric acids were used, which gave ee’s
up to 96%. The disadvantage of this method is the limited scope due as ester functionalities
are required.
At the University of Amsterdam the asymmetric PS-reaction has also been a subject of
research. In 2000 a method was published to synthesize enantiopure tetrahydro-β-carbolines
with the use of N-sulfinyl chiral auxiliaries on tryptamine8 which can be easily be removed
afterwards without sacrificing the ee (see 5 in figure 2). Seven years later a catalytic
asymmetric PS-reaction via N-sulfenyliminium ions in the presence of chiral binaphtyl
phosphoric acids was reported9. A year later the same method was applied for N-
benzyltryptamine10.
6
Figure 3: indole alkaloids with challenging stereochemistry
Recently, the enantioselective total synthesis of (-)-arboricine 6 was reported in extension of
this work11. This synthesis is concise and scalable and included the asymmetric PS-reaction
followed by a Pd(0)-catalyzed enolate cyclization. With (R)-3,3-triphenylsilyl-binol
phosphoric acid an ee of 78% was obtained and applying (R)-H8-binol phosphoric acid the ee
was raised to 89%. Because of the good results the research was extended to this
bachelorproject. The aim was to synthesize tetrahydro--carboline 12a from the Nb-
iodoolefin-functionalized tryptamine 9 and methyl 2,5-dioxopentanoate 10b followed by
Pd(0)-catalyzed enolate cyclization. This product can possibly be used as a precursor in the
synthesis of geissoschizine 7, mitragynine 2 and ajmalicine 8 (see figure 3).
Scheme 2: aim of the project
7
4. Results and Discussion
4.1 Synthesis of the functionalized tryptamine
The first step of the project was to synthesize the Nb-iodoolefin-functionalized tryptamine (see
scheme 3). First crotonaldehyde is iodinated with a convenient procedure12. Then the aldehyde
is reduced to an alcohol with NaBH4, followed by a mesylation of the alcohol with
methanesulfonyl chloride. This mesylate is then coupled to tryptamine with a yield of 70%,
based on the mesylate.
Scheme 3: synthesis of the Nb-iodoalkene-functionalized tryptamine
4.2 Synthesis of the aldehyde
Secondly the desired aldehyde had to be synthesized. The route is depicted in scheme 4.
Methyl 2-oxohex-5-enoate is synthesized through a Grignard reaction of 4-bromo-1-alkene
and dimethyloxalate. Because the yield of this reaction was unacceptably low (21%), it was
decided to proceed with ethyl 2-oxohex-5-enoate (75%) which is synthetically well
described13. Subsequently, the terminal alkene is converted into an aldehyde by ozonolysis
(for the mechanism see supp. 9.1). The low yield of the methyl ester 13a is probably due to
solubility problems of the reagent at –78 °C, since dimethyloxalate is a solid at rt while
diethyloxalate is a liquid at rt. Because the natural alkaloid compounds of interest contain a
methyl ester, product 13b was converted to the methyl ester via transesterification later on in
the project. This was performed in MeOH with 0.25 equiv. Et3N and was stirred for 55 min.
The desired product had formed, however the reaction was not optimized.
8
Scheme 4: synthesis route of aldehydes 10a and 10b
An alternative route to convert the terminal alkene into an aldehyde with OsO4 and NaIO4 was
investigated (for the mechanism see supp. 9.2). 2,6-lutidine was added to prevent the
formation of side products, but with this alkene the reaction did not work. The reaction did
work without 2,6-lutidine, only the yield was too low (33%) for this substrate to proceed with
this method14.
4.3 Pictet-Spengler reaction
The next step is the PS-reaction. The conditions are based on
earlier optimalization studies in our groupError: Reference source
not found. The catalyst (R)-3,3’-triphenylsilyl-binol phosphoric
acid ((R)-Tipsy, 2 mol%) was used and, most likely, the product
was obtained in the S-configuration. To remove the formed water
4Å molecular sieves were added. Toluene was chosen to be the
solvent and the reaction was stirred for 18 h at rt. The reaction gave the undesired product 15
instead of 11, because the keto-moiety of the α-keto-ester is very accessible for nucleophilic
attack of the indole-nitrogen. Chiral HPLC showed that the product was the racemate. The
low yield is due to purification difficulties because of a second unidentified product.
Scheme 5: Pictet-Spengler reaction of tryptamine 9 with aldehyde 10
9
Theory suggests that the ring-closed product is in equilibrium with the open structure under
basic conditions. To steer this equilibrium to the open form, it was attempted to put a Boc-
protection on the nitrogen with DMAP as catalyst and base. This reaction did not work,
because the Boc-group ended up on the oxygen of the hydroxy-group. A second attempt was
made by using potassium fenoxide as base and Pd(PPh3)4 as catalyst to perform the enolate-
iodoalkene coupling. This reaction worked neither. The same reaction was tried, only with
other bases, namely N,N-diisopropylethylamine and DBU, which both did not gave the
desired results.
Figure 4: 1H NMR spectra of 15 (lower) and 15b (upper)
In figure 4 the 1H NMR spectra of compounds 15 and 15b
are depicted. Trough 1H-1H-COSY spectroscopy the
signals could be attributed to their corresponding protons.
A remarkable shift of proton 15eq from 2.35 ppm to 3.15
ppm was observed. This was caused by the influence of
the Boc-substituent. Through a molecular model the relative stereochemistry could be
determined. When carbon atom 3 has the (S)-configuration, C16 has the (R)-configuration.
10
Scheme 6: synthesis of the keto-protected aldehyde 17
4.4 Synthesis of the aldehyde with keto-protection group
To prevent to formation of the undesired ring-closed product, the keto-moiety of the α-keto-
ester was protected with a diethyl acetal, using a mixture of triethylorthoformate and ethanol
catalyzed by H2SO4 in a yield of 68%. Then ozonolysis was applied to furnish the desired
aldehyde 17 in 71%. In order to achieve this, MeOH had to be added to DCM, otherwise 40%
of uncleaved ozonide 18 was obtained, which brought the yield down to only 34%.
Figure 5: side product of the ozonolysis of alkene 16
4.5 Pictet-Spengler reaction with aldehyde with protected keto-group
The PS-reaction with aldehyde 18 gave tetrahydro-β-carboline in a yield of 84% and the ee
was also raised to 53%. However this result is still unsatisfactory. If (S)-Tipsy is used as
catalyst the ee drops to 42%. This is a surprising result and is maybe due to temperature or the
addition sequence. The experiment with (R)-Tipsy 14 was performed at 0 °C and the aldehyde
was added last, however, the experiment with (S)-Tipsy was at rt and the aldehyde was added
as first.
Scheme 7: Pictet-Spengler reaction of tryptamine 9 with aldehyde 17
11
The next step is Boc-protection of the indole nitrogen to avoid the undesired ring-closing
reaction after hydrolysis of the acetal. It also prevents possible racemization via acid-
catalyzed scission of the bond between the asymmetric carbon atom and Nb or a retro PS
process. Boc2O and DMAP were added to 20 in DCM to furnish acetal 21 in 95% yield.
Scheme 8: N-Boc protection of 20 and acetal deprotection of 21
4.6 Hydrolysis of acetal
In order to perform the Pd(0)-catalyzed iodoalkene/enolate cyclization the acetal protecting
group had to be removed, because a ketone at C16 is necessary for this reaction. Acetals are
generally hydrolysed with an acid in water/acetone or water/EtOH. However, for this specific
acetal this method gave complications. In table 1 different conditions are showed. The
conversion is measured by 1H NMR. The first problem is the slow rate of the reaction. This is
presumably due to the basic nitrogen which takes up the first equivalent of acid. This is in
combination with the electron withdrawing ester group next to the acetal which does not
stabilize the oxoniumion as an intermediate of the hydrolysis. The other problem is a low
recovery which indicates a carboxylic acid formation from the hydrolysis of the ester. This
causes the molecule to move into the waterlayer under basic workup conditions. In the end the
hydrolysis of the acetal was not achieved. Table 1: Reaction condition for the hydrolysis of acetal 21
12
Condition Solvent Acid Conversion?a Acetone H2SO4 (2.5 equiv.) Yes, ± 30% after three days b EtOH H2SO4 (3 equiv.) No c EtOH / Acetone H2SO4 (25 equiv.) Yes, ± 20% after two days d Acetone / H2O H2SO4 (2.5 equiv.) Noe EtOH HCl (20 vol.%) Yes, ± 20% after two days
5. Conclusion and Outlook
Several new aldehydes were successfully synthesized via a Gringard reaction of 4-bromo-1-
butene and dimethyloxalate and diethyloxalate followed by ozonolysis. The yield of ethylester
13b was much higher so it was chosen to proceed with this compound for the rest of the
research.
When aldehyde 10 was applied in the Pictet-Spengler reaction catalyzed by (R)-Tipsy, the
undesired ring-closed product 15 was formed by nucleophilic attack of the indole-nitrogen on
the keto moiety of the α-keto-ester. This product was obtained as a racemic mixture. There is
no evidence for an equilibrium between the closed and the open form, so it was decided to go
on with another aldehyde.
To avoid the formation of the undesired product 15, the keto moiety was protected with a
diethylacetal. Now the desired product 20 was formed in the PS-reaction catalyzed by (R)-
Tipsy in 53% ee, using (S)-Tispy was the ee dropped to 43%. This difference is probably
caused by influences of the addition sequence and/or the temperature. The ee is still not
satisfactory and might be improved by using another catalyst or another protecting group on
the ketone.
A Boc-protecting group was installed on the indole-nitrogen to prevent formation of the
undesired ring-closed product and racemization during hydrolysis of the acetal. The removal
of the acetal turned out to be difficult and is not achieved. Different acid catalyzed conditions
were tested, however none of them worked properly. The reaction is very slow due to a basic
nitrogen in the molecule, which takes up the first equivalent of acid in combination with the
electron withdrawing ester group next to the acetal, which does not stabilize the oxonium-ion.
Also the recovery of the reaction is low, which indicated the hydrolysis of the ester.
To succeed in the hydrolysis of the acetal other methods should be tried, like for instance the
Lewis acid Me2BBr15. Also other protecting groups could make the hydrolysis easier,
although diethylacetals are some of the easiest removable protecting groups.
13
6. Experimental Section
General Remarks
All 1H NMR and 13C NMR spectra (APT) were recorded with a Bruker Avance 400
spectrometer (1H 400 MHz, 13C 100 MHz) at room temperature in CDCl3. Analytical thin
layer chromatography was performed using a Merck TLC plastic roll 500 x 20 cm silica gel
60 F254. Flash chromatography was performed on Biosolve 60Å (0.032-0.063 mm) silica gel.
Chiral columns include Chiracel® OD (Chiral Technologies Europe, 0.46 cm x 25 cm),
Chiralpak® AD (Chiral Technologies Europe, 0.46 cm x 25 cm) and Chiralcel® OD-H (Chiral
Technologies Europe, 0.46 cm x 25 cm) columns.
Solvents were obtained from Biosolve. Toluene (used for the Pictet-Spengler reaction) was
stored under 4 Å molecular sieves. Commercial reagents were purchased from Biosolve,
Sigma-Aldrich, Fluka or Acros and used as received. Powdered molecular sieves (Aldrich)
were dried at 200 ºC and 0.1 mbar. (R)-BINOL phosphoric acid ((R)-Tipsy) was prepared
according to a literature procedure16. (S)-BINOL phosphoric acid ((S)-Tipsy) was obtained
from Aldrich.
lsj 2 Z-2-iodo-2-butene-1-ol mesylate
Methanesulfonyl chloride (0.85 mL, 11 mmol) was added drop wise to a
solution of 2-iodo-2-butene-1-ol (1.98 g, 10 mmol) and Et3N (1.66 mL,
11.8 mmol) in DCM (40 ml) at 0 ºC. After 2 h the reaction was extracted
with water and NaHCO3 solution. The mesylate was obtained by drying with NaSO4 and
evaporation of the solvent. The product was sufficiently pure for the next step. 1H NMR
6.22 (q, J = 6.4 Hz, 1H), 4.92 (s, 2H), 3.09 (s, 3H), 1.86 (d, J = 6.4 Hz, 3H).
lsj 3 N-(Z-2-iodo-2-butenyl)-tryptamine 9
Z-2-iodo-2-butene-1-ol mesylate (1.31 g, 5 mmol) was added to
a solution of tryptamine (1.12 g, 7 mmol) in a mixture of DCM
(30mL) and 20% NaOH (10 mL). The mixture was stirred for 2
h at rt and the waterlayer was removed and extracted with
DCM. The combined organic layer was dried with NaSO4 and
the solvent was evaporated. Chromatograpy (PE 60/80 / EtOAc = 1:1 EtOAc) gave 9 (1.2
g, 3.52 mmol, 70%) as a brown syrup, which solidified upon standing. 1H NMR 8.00 (s, 1H-
14
H1), 7.63 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.21 (m, 1H), 7.13 (m, 1H), 7.09 (d, J
= 2.3 Hz, 1H- H7), 5.78 (q, J = 6.3 Hz, 1H- H19), 3.5 (s, 2H- H21), 2.99 ( t, J = 7.0 Hz, 2H),
2.86 (m, 2H), 1.76 (d, 6.3 Hz, 3H- H18).
lsj 6 Methyl 2-oxohex-5-enoate 13aError: Reference source not found
To a dry flask containing magnesium (2.5 g, 104 mmol) was added
a solution of 4-bromo-1-butene (4.5 mL, 44.3 mmol) in dry THF
(40 ml) drop wise with vigorously stirring in 30 minutes at rt. This
solution was then added drop wise in 10 minutes to a mixture of diethyl oxalate (5.23 g, 44.3
mmol), dry THF (60 mL) and dry ether (70 mL) at -78 ºC. The reaction was stirred for 4 h
and then quenched with sat. NH4Cl-solution. The mixture was partitioned with EtOAc (3 x 50
mL). The combined organic phases were dried with NaSO4 and the solvent was evaporated.
The product was purified with chromatography (PE 60/80 / EtOAc = 3:1) to furnish a pale
yellow liquid (1.3 g, 9.14 mmol, 21%). 1H NMR 5.78-5.87 (m, 1H- H2), 5.02-5.11 (m, 2H-
H1), 3.89 (s, 3H- H7), 2.98 (t, J = 7.3 Hz, 2H- H4), 2.41 (m, 2H- H3).
lsj 5 Ethyl 2-oxohex-5-enoate 13bError: Reference source not found
To a dry flask containing magnesium (2.5 g, 104 mmol) was
added a solution of 4-bromo-1-butene (4.5 mL, 44.3 mmol) in
dry THF (40 ml) drop wise with vigorously stirring in 30
minutes at rt. This solution was then added drop wise in 20 minutes to a mixture of diethyl
oxalate (5.0 mL, 36.8 mmol), dry THF (25 mL) and dry ether (50 mL) at -78 ºC. The reaction
was stirred for 4 h and then quenched with sat. NH4Cl-solution. The mixture was partitioned
with EtOAc (3 x 50 mL). The combined organic phases were dried with NaSO4 and the
solvent was evaporated. The product was purified with chromatography (PE 60/80 / EtOAc =
3:1) to furnish a pale yellow liquid (4.3 g, 27.53 mmol, 75%). 1H NMR 5.84 (ddt, J = 16.8
Hz, 10.3 Hz, 6.7 Hz, 1H- H2), 5.05 (m, 2H- H1), 4.34 (q, J = 7.1 Hz, 2H- H7), 2.97 (t, J = 7.2
Hz, 2H- H4), 2.40 (m, 2H- H3), 1.39 (t, J = 7.2 Hz, 3H- H8).
lsj 16 Methyl 2,5-dioxopentanoate 10a
Methyl 2-oxohex-5-enoate (0.3 g, 2.11 mmol) was dissolved in
DCM and cooled to -78 ºC. Ozone was bubbled trough the solution
until it turned blue. Dimethylsulfide (1.6 mL, 21.1 mmol) was
added and the reaction was stirred overnight at rt. The product was purified with
15
chromatography (PE 60/80 / EtOAc = 2:1 EtOAc) to furnish a pale yellow liquid (0.2 g,
1.39 mmol, 66%). 1H NMR 9.82 (s, 1H- H2), 3.92 (s, 3H- H7), 3.18 (m, 2H- H3), 2.90 (m,
2H- H4).
lsj 9 Ethyl 2,5-dioxopentanoate 10b method OsO4
To a solution of ethyl 2-oxohex-5-enoate (0.3 g, 1.92 mmol) in a
mixture of dioxane (15 mL) and water (5 mL) NaIO4 (1.78 g,
7.68 mmol) was added together with a 0.97 mL of a (4 w/v%)
solution of OsO4 in water. After the mixture was stirred for 28 h at rt, CH2Cl2 (50 mL) and
water (15 mL) were added. The water phase was removed and extracted with CH2Cl2 and the
organic phase was washed with brine. The combined organic layers were dried with NaSO4
and the solvent was removed. Chromatography (PE 60/80 / EtOAc = 1:1) gave 10b as a pale
yellow liquid (0.1 g, 0.63 mmol, 33%). 1H NMR 9.84 (s, 1H- H2), 4.36 (q, J = 7.2, 2H- H7),
3.18 (m, 2H- H3), 2.89 (t, J = 6.4, 2H- H4), 1.39 (t, J = 7.1 Hz, 3H- H8).
lsj 10 Ethyl 2,5-dioxopentanoate 10b method ozonolysis
Ethyl 2-oxohex-5-enoate (0.63 g, 4.0 mmol) was dissolved in DCM and cooled to -78 ºC.
Ozone was bubbled trough the solution until it turned blue. Dimethylsulfide (2.9 mL, 40
mmol) was added and the reaction was stirred overnight at rt. The product was purified with
chromatography (PE 60/80 / EtOAc = 2:1 PE 60/80 / EtOAc = 1:1) to furnish a pale
yellow liquid (0.45 g, 2.85 mmol, 71%). 1H NMR 9.84 (s, 1H), 4.36 (q, J = 7.2, 2H), 3.18
(m, 2H), 2.89 (t, J = 6.4, 2H), 1.39 (t, J = 7.1 Hz, 3H).
lsj 18 Pictet-Spengler reaction with tryptamine 9 and aldehyde 10a
A mixture of N-(Z-2-iodo-2-butenyl)-tryptamine 9 (0.21 g, 0.64 mmol), 4 Å molecular sieves
(1 g, powdered and dried at 200 ºC / 0.1 mbar) and (R)-3,3’-bis(triphenylsilyl)-
binolphosphoric acid (0.011 g, 0.128 mmol, 2%) in toluene (7 mL) was stirred at rt for 5
minutes. Methyl 2,5-dioxopentanoate (0.2 g, 1.28 mmol) was added and the reaction was
stirred overnight. The molecular sieves were removed by filtration over Celite® using EtOAc
and the solvents were evaporated. It was necessary to purify the product twice with
chromatography (PE 60/80 / EtOAc = 2:1 PE 60/80 / EtOAc = 1:1) to furnish an impure
yellow glass (0.094 g, 0.20 mmol, 31%).
lsj 13 Pictet-Spengler reaction with tryptamine 9 and aldehyde 10b
16
A mixture of N-(Z-2-iodo-2-butenyl)-tryptamine 9 (0.65 g, 1.9
mmol), 4 Å molecular sieves (3 g, powdered and dried at 200
ºC / 0.1 mbar) and (R)-3,3’-bis(triphenylsilyl)-
binolphosphoric acid (0.016 g, 0.019 mmol, 1%) in toluene
(20 mL) was stirred at rt for 5 minutes. Ethyl 2,5-
dioxopentanoate (0.44 g, 2.8 mmol) was added and the
reaction was stirred overnight. The molecular sieves were
removed by filtration over Celite® using EtOAc and the solvents were evaporated. It was
necessary to purify the product twice with chromatography (1: PE 60/80 / EtOAc = 2:1
EtOAc, 2: PE 60/80 / EtOAc / Et3N = 1:1:0.02) to furnish 15b as a yellow glass (0.27 g, 0.56
mmol, 30%). Ee: racemic mixture determined on a Chiralcel® AD column, heptane:iso-
propanol = 90:10, 0.5 mL/min, tr 1 = 25.5 min, tr 2 = 28.8 min). 1H NMR 7.46 (m, 1H-
H12), 7.35 (m, 1H- H9), 7.11 (m, 2H- H10/11), 6.02 (q, J = 6.4 Hz, 1H- H19), 4.71 (s, 1H-
H24), 4.03-4.12 (m, 2H- H22), 3.79 (m, 1H- H21), 3.70 (m, 1H- H3), 3.28 (m, 1H- H5), 3.20
(d, J = 14.4 Hz, 1H- H21), 2.90 (m, 1H- H6), 2.71 (m, 1H- H6), 2.62 (dt, J = 11.4 Hz, 4.4 Hz,
1H- H5), 2.37 (m, 2H- H15), 2.26 (m, 1H- H14eq), 1.90 (m, 1H- H14ax), 1.85 (d, J = 6.4 Hz,
3H- H18), 0.94 (t, J = 7.1 Hz, 3H- H23). 13C NMR 171.97, 136.58, 135.44, 131.95, 131.43,
120.23, 117.96, 111.41, 108.10, 107.68, 83.91, 64.18, 62.68, 56.84, 49.46, 35.47, 25.21,
21.72, 20.95, 13.58.
lsj 14 Boc-protecting group on oxygen of hydroxy-group of 15b
A solution of Pictet-Spengler product 15b (0.09 g, 0.19mmol), Boc2O (0.07 g, 0.33 mmol)
and DMAP (0.005g, 0.039 mmol, 20mol%) in DCM (4 mL) was stirred overnight at rt. The
solvent was evaporated and after recrystallization from DCM and PE 60/80, the product was
isolated as a yellow solid (0.067 gr, 0.12 mmol, 59%). 1H NMR 7.60 (m, 1H- H12), 7.42
(m, 1H- H9), 7.13 (m, 2H- H10/11), 5.97 (q, J = 6.4 Hz, 1H- H19), 4.06-4.15 (m, 2H- H22),
3.77 (d, J = 14.4 Hz, 1H- H21), 3.69 (m, 1H- H3), 3.27 (m, 1H- H5), 3.16 (m, 2H- H21/15 eq),
2.86 (m, 1H- H6), 2.66 (m, 1H- H6), 2.56 (dt, J = 11.6 Hz, 4.4 Hz, 1H- H5), 2.48 (dt, J = 14.2
Hz, 3.4 Hz, 1H- H15ax), 2.32 (m, 1H- H14eq), 2.06 (m, 1H- H14ax), 1.83 (d, J= 6.3 Hz, 3H-
H18), 1.59 (s, 9H), 1.08 (t, J = 7.1 Hz, 3H- H23).
lsj 22 ethyl 2,2-diethoxyhex-5-enoate17
17
H2SO4 (0.082 mL) was added to a mixture of ethyl 2-oxohex-5-
enoate (5.82 g, 37.26 mmol), triethylorthoformate (29.1 mL) and
EtOH (23.3 mL). This mixture was stirred for 14 h at rt and
extracted with Et2O (35 mL) and NaHCO3 (20 mL). The
waterlayer was extracted with Et2O (35 ml) and the combined
organic phases were washed with brine and dried with MgSO4. The solvents were evaporated
to furnish a colourless oil (5.8 g, 25.2 mmol, 68%). 1H NMR 5.80 (m, 1H- H2), 5.03 (m,
2H- H1), 4.27 (q, J = 7.2 Hz, 2H- H6), 3.55 (m, 4H- H9), 2.00(s, 4H- H2/3), 1.33 (t, J = 7.2,
3H- H8), 1.26 (t, J = 6.8, 6H- H10). 13C NMR 169.04, 137.02, 114.50, 101.42, 61.07, 57.44,
33.31, 27.24, 14.92, 13.99.
lsj 23 ethyl 2,2-diethoxyhex-5-oxopentanoate
Ethyl 2,2-diethoxyhex-5-enoate (0.47 g, 2.06 mmol) was
dissolved in DCM (50 mL) and cooled to -78 ºC. Ozone was
bubbled trough the solution until it turned blue. Dimethylsulfide
(1.5 mL, 20.6 mmol) was added and the reaction was stirred
overnight at rt. The product was purified with chromatography
(PE 60/80 / EtOAc = 3:1) to furnish 17 as a colourless liquid (0.156 g, 0.68 mmol, 34%). 1H
NMR 9.76 (t, J = 1.2 Hz, 1H- H2), 4.26 (q, J = 7.1 Hz, 1H- H7), 3.59-3.45 (m, 4H- H9),
2.41 (m, 2H- H3), 2.14 (m, 2H-H4), 1.33 (t, J = 7.1 Hz, 3H- H8), 1.24 (t, J = 7.0 Hz, 6H-
H10). 13C NMR 200.32, 168.71, 100.82, 61.29, 57.76, 37.92, 26.62, 14.85, 13.91.
With this procedure side product 18 is formed in 40%
yield. 1H NMR 5.20 (m, 1H- H2), 5.18 (s, 1H- H1), 5.06
(s,1H- H1), 4.27 (q, J = 7.2 Hz, 2H- H7), 3.44-3.59 (m,
4H- H9), 2.03 (m, 2H), 1.74 (m, 2H), 1.33 (t, J = 7.2 Hz,
3H- H8), 1.24 (t, J = 7.1 Hz- H10). 13C NMR 168.82,
102.57, 101.162, 93.96, 61.36, 57.70, 57.67, 28.09, 25.37, 14.96, 14.06. The protons of C1
give two singlets in 1H NMR at 5.18 ppm and 5.06 ppm. This corresponds to results in
literature18.
lsj 23.4 ethyl 2,2-diethoxyhex-5-oxopentanoate
18
Ethyl 2,2-diethoxyhex-5-enoate (0.5 g, 2.17 mmol) was dissolved in DCM (35 mL) and
MeOH (7 mL) and cooled to -78 ºC. Ozone was bubbled trough the solution until it turned
blue. Dimethylsulfide (1.6 mL, 21.7 mmol) was added and the reaction was stirred overnight
at rt. The product was purified with chromatography (PE 60/80 / EtOAc = 2:1) to furnish 17
as a colourless liquid (0.36 g, 1.54 mmol, 71%). 1H NMR 9.76 (t, J = 1.2 Hz, 1H), 4.26 (q, J
= 7.1 Hz, 1H), 3.59-3.45 (m, 4H), 1.33 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.0 Hz, 6H). 13C NMR
200.32, 168.71, 100.82, 61.29, 57.76, 37.92, 26.62, 14.85, 13.91.
lsj 25 Pictet-Spengler product with aldehyde 17
Ethyl 2,2-diethoxyhex-5-oxopentanoate (0.16 g, 0.68 mmol)
was dissolved in toluene (3,5 mL) and N-(Z-2-iodo-2-butenyl)-
tryptamine 9 (0.16 g, 0.46 mmol), 4 Å molecular sieves (0.34
g, powdered and dried at 200 ºC / 0.1 mbar) were added. At
last (R)-Tipsy (0.006 g, 0.007 mmol, 2 mol%) was added and
the reaction was stirred for 24 h at rt. The molecular sieves
were removed by filtration over Celite® using EtOAc and the
solvents were evaporated. The product was purified with chromatography (PE 60/80 / EtOAc
= 3:1) to furnish a colourless oil (0.17 g, 0.31 mmol, 68%). Ee: 51% determined on a
Chiralcel® AD column, heptane:iso-propanol = 90:10, 0.5 mL/min, tr major = 8.5 min, tr
minor = 10.3 min). 1H NMR 7.98 (s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7,32 (d, J = 7.9 Hz, 1H),
7.08-7.18 (m, 2H), 5.85 (q, J = 6.4 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.69 (t, J = 6.3 Hz, 1H),
3.49-3.65 (m, 4H), 3.40 (m, 2H), 3.18 (m, 1H), 2.86 (m, 2H), 2.60 (m, 1H), 2.13-2.22 (m,
2H), 1.83 (d, J = 6.3 Hz, 3H), 1.76 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H) 1.26 (t, J = 3.6 Hz, 3H). 13C NMR 169.69, 135.72, 134.74, 131.81, 127.03, 121.74, 118.98, 117.84, 110.65, 110.10,
107.94, 107.92, 102.23, 64.87, 61.32, 57.92, 57.72, 56.03, 55.99, 43.74, 31.43, 28.27, 21.63,
17.90, 15.13, 14.19.
lsj 30 Pictet-Spengler product with aldehyde 17 at 0 °C
A mixture of N-(Z-2-iodo-2-butenyl)-tryptamine 9 (0.28g, 0.82 mmol), 4 Å molecular sieves
(1.0 g, powdered and dried at 200 ºC / 0.1 mbar) and (R)-Tipsy (0.014 g, 0.016 mmol, 2 mol
%) in toluene (6 mL) was stirred for 20 minutes at 0 ºC. Ethyl 2,2-diethoxyhex-5-
oxopentanoate (0.30 g, 1.29 mmol) was added and the reaction was stirred for 24 h at 0 ºC.
The molecular sieves were removed by filtration over Celite® using EtOAc and the solvents
were evaporated. The product was purified with chromatography (PE 60/80 / EtOAc = 4:1) to
19
furnish a colourless oil (0.38 g, 0.69 mmol, 84%). Ee= 53% determined on a Chiralcel® AD
column, heptane:iso-propanol = 95:5, 0.5 mL/min, tr major = 10.8 min, tr minor = 14.5 min).
lsj 26 N-Boc protection of 20
To a mixture of compound 20 (0.38 g, 0.69 mmol) and Boc2O (0.26 g, 1.17 mmol) in DCM (4
mL) DMAP (0.017 g, 0.14 mmol, 20 mol%) was added. The reaction was stirred for 17 h at
rt. The solvents were evaporated and the product was purified with chromatography (PE
60/80 / EtOAc = 5:1) to yield a colourless oil (0.43 g, 0.65 mmol, 94 %). 1H NMR 8.12 (d, J
= 8.0 Hz, 1H), 7.40 (d, J = 6.6 Hz, 1H), 7.21-7.30 (m, 2H), 5.80 (q, J = 6.3 Hz, 1H), 4.17-4.29
(m, 2H), 4.10 (m, 1H), 3.65 (m, 2H), 3.50 (m, 2H), 3.42 (dd, J = 19.0 Hz, 3.7 Hz, 2H), 3.19
(m, 1H), 2.94 (dd, J = 14.1 Hz, 5.9 Hz, 1H), 2.77 (m, 1H), 2.59 (m, 1H), 2.48 (dd, J = 16.5
Hz, 4.9 Hz, 1H), 2.02 (m, 1H), 1.82 (d, J = 6.4 Hz, 3H), 1.76 (m, 1H), 1.67 (s, 9H), 1.53 (m,
1H), 1.22-1.32 (m, 6H). 13C NMR 169.55, 149.99, 136.71, 135.74, 131.94, 129.20, 123.77,
122.40, 117.60, 115.54, 113.90, 110.21, 102.05, 83.34, 64.88, 61.00, 57.82, 57.38, 56.72,
40.23, 32.38, 28.12, 28.06, 21.60, 16.76, 15.13, 14.18.
1 Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797-18422 Chopra, R. N.; Gupta, J. C.; Mukherjee, B. Indian J. Med. Res. 1933, 21, 2613 Takayama, H.; Ishikawa, H.; Kurihara, M.; Kitajima, M.; Aimi, N.; Ponglux, D.; Koyama, F.; Matsumoto, K.; Moriyama, T.; Yamamoto, L. T.; Watanabe, K.; Murayama, T.; Horie, S. J. Med. Chem. 2002, 45, 1949-19564 Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030-20365 Kawate, T.; Yamada, H.; Soe, T.; Nakagawa, M. Tetrahedron: Asymmetry 1996, 7, 1249-12526 Taylor, M. S.; Jacobson, E. N. J. Am. Chem. Soc. 2004, 126, 10558-105597 Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086-10878 Gremmen, C.; Willemse, B.; Wanner, M. J.; Koomen, G.-J. Org. Lett. 2000, 2, 1955-19589 Wanner, M. J.; van der Haas, R. N. S., de Cuba, K. R.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem. Ed. 2007, 46, 7485-748710 Sewgobind, N. V.; Wanner, M. J.; Ingemann, S.; de Gelder, R.; van Maarseveen, J. H.; Hiemstra, H. J. Org. Chem. 2008, 73, 6405-640811 Wanner, M. J.; Boots, R. N. A.; Eradus, B.; de Gelder, R.; van Maarseveen, J. H.; Hiemstra, H. Org. Lett. 2009, 11, 2579-258112 Krafft, M. E.; Cran, J. W. Synlett 2005, 1263-126613 Macritchie, J. A.; Silcock, A.; Willis, C. L. Tetrahedron: Asymmetry 1997, 8, 3895-390214 Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217-321915 Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996, 61, 5418-542416 Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84-8617 Trost, B. M.; Fettes, A.; Shireman, B. T. J. Am. Chem. Soc. 2004, 126, 2660-2661 18 McCullough, K. J.; Sugimoto, T.; Tanaka, S.; Kusabayashi, S.; Nojima, M. J. Chem. Soc. Perkin Trans. 1, 1994, 6, 643-651
20
Hydrolysis of acetal 21 general procedure
2 ml of a stock solution of the acid in the solvent are added to acetal 21 (0.050 g, 0.076
mmol). For the conditions see §4.6. The reaction is followed with 1H NMR. The appearance
of a quartet at 4.2/4.4 ppm was noticed and it is thought that this signal belongs to protons 22
of product 22.
21
7. Acknowledgements
I would like to thank Martin Wanner for his guidance and daily supervision and Prof. Henk
Hiemstra for giving me the opportunity to work in his research group. And all members of the
Synthetic Organic group who helped me with my problems.
8. List of abbreviations
DCM dichloromethane
DMAP 4-dimethylaminopyridine
DMS dimethylsulfide
EtOAc Ethylacetate
EtOH Ethanol
MeOH Methanol
NMR Nuclear Magnetic Resonance
THF Tetrahydrofuran
rt Roomtemperature
22
9. Supplementary
9.1 Mechanism ozonolysis19
Scheme 9
The ozonolysis consists of several cycloadditions to eventually give an ozonide. This
explosive intermediate is cleaved into two aldehydes with dimethylsulfide.
9.2 Mechanism osmiumtetroxide / periodate olefin cleavageError: Reference source not found
Scheme 10
The first step is a cycloaddition of OsO4 to the double bond to form the osmate ester. This
ester is hydrolyzed to the diol. This diol is then cleaved with NaIO4 into two aldehydes. NaIO4
also oxidizes osmium back to its original oxidation state so the expensive and toxic osmium
can be added in catalytic amounts.
19 Clayden, Greeves, Warren and Wothers, 'Organic Chemistry', Oxford University Press, ISBN 0 19 850346 6
23
9.3 Spectra
12
ppm (f1)1.02.03.04.05.06.07.08.0
24
15
ppm (f1)1.02.03.04.05.06.07.0
34
ppm (f1)1.02.03.04.05.06.07.08.09.0
25
14
ppm (f1)1.02.03.04.05.06.07.0
23
ppm (f1)1.02.03.04.05.06.07.08.09.0
26
48
ppm (f1)1.02.03.04.05.06.07.0
40
ppm (f1)1.02.03.04.05.06.07.0
27
1
ppm (f1)1.02.03.04.05.06.07.0
28
47
ppm (f1)1.02.03.04.05.06.07.0
75
ppm (f1)50100150
29
70
ppm (f1)1.02.03.04.05.06.07.08.09.0
54
ppm (f1)050100150200
30
55
ppm (f1)1.02.03.04.05.06.07.08.0
56
ppm (f1)50100150
31
80
ppm (f1)1.02.03.04.05.06.07.08.0
58
ppm (f1)50100150
32
+ triethylorthoformate+ ethyl acetate
64
ppm (f1)1.02.03.04.05.06.07.0
72
ppm (f1)50100150
33
10. References
34