1.
It was attempted to synthesize new indole alkaloids via the asymmetric Pictet-Spengler reaction (PS) of N b
-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.
Er is een poging gedaan om nieuwe indool alkaloïden te synthetiseren met behulp van de asymmetrische Pictet-Spengler reactie van aldehyde 10 met N b
-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.
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.
2

1. Abstract
2. Samenvatting en populaire samenvatting
3. Introduction
4. Results and Discussion
4.1 Synthesis of the functionalized tryptamine
4.2 Synthesis of the aldehyde
4.3 Pictet-Spengler reaction p. 2 p. 2 p. 4 p. 7 p. 7 p. 7 p. 8
4.4 Synthesis of the aldehyde with keto-protection group p. 10
4.5 Pictet-Spengler reaction with aldehyde with protected keto-group p.10 p. 11 4.6 Hydrolysis of the acetal
5. Conclusion and Outlook p. 12
6. Experimental section p. 13
7. Acknowledgement
8. List of abbreviations
9. Supplementary
9.1 Mechanism of ozonolysis
9.2 Mechanism osmiumtetroxide / periodate olefin cleavage
9.3 Spectra
10. References p. 20 p. 20 p. 21 p. 21 p. 21 p. 22 p. 32
3

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 bases 1 . In figure 1 two examples of biologically active indole alkaloids are depicted. Reserpine
2
1 exhibits a cardiovascular effect and mitrgynine 3 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 Spengler
4
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.
N
H
HN
R
1
-H
2
O
N
H
N
R
1
R
2
N
H H
R
2
N
R
1
N
H
R
2
N
R
1
R
2
O
H
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
4

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.
CO
2
Et
NH
CO
2
Et
N
H
N
R O
N
H
R
N
H
R
N
O
S
Ar
3 4 5
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 all
5
. 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
Jacobsen
6
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 coworkers
7
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 tryptamine 8 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 reported
9
. A year later the same method was applied for N benzyltryptamine
10
.
5

Figure 3: indole alkaloids with challenging stereochemistry
Recently, the enantioselective total synthesis of (-)-arboricine 6 was reported in extension of this work
11
. 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)-H
8
-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 N b
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
6

4.1 Synthesis of the functionalized tryptamine
The first step of the project was to synthesize the N b
-iodoolefin-functionalized tryptamine
(see scheme 3). First crotonaldehyde is iodinated with a convenient procedure
12
. Then the aldehyde is reduced to an alcohol with NaBH
4
, 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.
O
H
I
2
, K
2
CO
3
, cat. DMAP
H
2
O / THF
I
O
H
NaBH
4
MeOH I
OH
MsCl, NEt
3
DCM
NH
2
N
H
70%
HN
I
N
H
1.4 equiv.
9
DCM / 20% NaOH
I
~100%
OMs
Scheme 3: synthesis of the N b
-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 described
13
. 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. Et
3
N and was stirred for 55 min.
The desired product had formed, however the reaction was not optimized.
7

Scheme 4: synthesis route of aldehydes 10a and 10b
An alternative route to convert the terminal alkene into an aldehyde with OsO
4
and NaIO
4
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 method
14
.
4.3 Pictet-Spengler reaction
The next step is the PS-reaction. The conditions are based on earlier optimalization studies in our group
Ошибка! Закладка не определена.
. 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
8

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 Bocprotection 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(PPh
3
)
4
as catalyst to perform the enolateiodoalkene 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: 1 H NMR spectra of 15 (lower) and 15b (upper)
In figure 4 the
1
H NMR spectra of compounds 15 and 15b are depicted. Trough 1 H1 H-COSY spectroscopy the I
RO
O
N
16
15
OEt
3
14
N
21
15 : R=H
15b : R=Boc signals could be attributed to their corresponding protons.
A remarkable shift of proton 15 eq
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.
9

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-ketoester was protected with a diethyl acetal, using a mixture of triethylorthoformate and ethanol catalyzed by H
2
SO
4
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
10

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 acidcatalyzed scission of the bond between the asymmetric carbon atom and N b
or a retro PS process. Boc
2
O 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
1
H 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.
c d e a b
Condition Solvent Acid Conversion?
Acetone
EtOH
H
2
SO
4
(2.5 equiv.) Yes, ± 30% after three days
H
2
SO
4
(3 equiv.) No
EtOH / Acetone H
2
SO
4
(25 equiv.) Yes, ± 20% after two days
Acetone / H
EtOH
2
O H
2
SO
4
(2.5 equiv.) No
HCl (20 vol.%) Yes, ± 20% after two days
Table 1: Reaction condition for the hydrolysis of acetal 21
11

Several new aldehydes were successfully synthesized via a Gringard reaction of 4-bromo-1butene 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 Me
2
BBr
15
. Also other protecting groups could make the hydrolysis easier, although diethylacetals are some of the easiest removable protecting groups.
12

General Remarks
All 1 H NMR and 13 C NMR spectra (APT) were recorded with a Bruker Avance 400 spectrometer ( 1 H 400 MHz, 13 C 100 MHz) at room temperature in CDCl
3
. Analytical thin layer chromatography was performed using a Merck TLC plastic roll 500 x 20 cm silica gel
60 F
254
. 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 procedure
16
. (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 Et
3
N (1.66 mL,
11.8 mmol) in DCM (40 ml) at 0 ºC. After 2 h the reaction was extracted with water and NaHCO
3
solution. The mesylate was obtained by drying with NaSO
4
and evaporation of the solvent. The product was sufficiently pure for the next step.
1
H 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 NaSO
4
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.
1
H NMR

8.00 (s, 1H-
13

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 13a
13
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. NH
4
Cl-solution. The mixture was partitioned with EtOAc (3 x 50 mL). The combined organic phases were dried with NaSO
4
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%). 1 H 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 13b
13
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. NH
4
Cl-solution. The mixture was partitioned with EtOAc (3 x 50 mL). The combined organic phases were dried with NaSO
4
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%).
1
H 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
14

chromatography (PE 60/80 / EtOAc = 2:1

EtOAc) to furnish a pale yellow liquid (0.2 g,
1.39 mmol, 66%).
1
H 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 OsO
4
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) NaIO
4
(1.78 g,
7.68 mmol) was added together with a 0.97 mL of a (4 w/v%) solution of OsO
4
in water. After the mixture was stirred for 28 h at rt, CH
2
Cl
2
(50 mL) and water (15 mL) were added. The water phase was removed and extracted with CH
2
Cl
2
and the organic phase was washed with brine. The combined organic layers were dried with NaSO
4 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%). 1 H 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 E thyl 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%).
1
H 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%).
15

lsj 13 Pictet-Spengler reaction with tryptamine 9 and aldehyde 10b
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 2,5dioxopentanoate (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 / Et
3
N = 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:isopropanol = 90:10, 0.5 mL/min, t r
1 = 25.5 min, t r
2 = 28.8 min).
1
H 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- H14 eq
), 1.90 (m, 1H- H14 ax
), 1.85 (d, J = 6.4 Hz,
3H- H18), 0.94 (t, J = 7.1 Hz, 3H- H23).
13
C 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), Boc
2
O (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%).
1
H 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- H15 ax
), 2.32 (m, 1H- H14 eq
), 2.06 (m, 1H- H14 ax
), 1.83 (d, J = 6.3 Hz, 3H-
H18), 1.59 (s, 9H), 1.08 (t, J = 7.1 Hz, 3H- H23).
16

lsj 22 ethyl 2,2-diethoxyhex-5-enoate 17
1
2
O
4
5
3
9
O O
6 O
7
8
H
2
SO
4
(0.082 mL) was added to a mixture of ethyl 2-oxohex-5enoate (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 Et
2
O (35 mL) and NaHCO
3
(20 mL). The
10 waterlayer was extracted with Et
2
O (35 ml) and the combined organic phases were washed with brine and dried with MgSO
4
. The solvents were evaporated to furnish a colourless oil (5.8 g, 25.2 mmol, 68%).
1
H 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).
13
C 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
O
2
O
4
5
3
9
O O
6 O
7
8
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
10 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%). 1 H
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).
13
C 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.
1
H NMR

5.20 (m, 1H- H2), 5.18 (s, 1H- H1), 5.06 H
H
O
1
O
O
2
3
O
4
O O
O
7
9
10
8
(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).
13
C 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
1
H NMR at 5.18 ppm and 5.06 ppm. This corresponds to results in literature
18
.
17

lsj 23.4 ethyl 2,2-diethoxyhex-5-oxopentanoate
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%).
1
H 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).
13
C 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, t r
major = 8.5 min, t r minor = 10.3 min).
1
H 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).
13
C 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-5oxopentanoate (0.30 g, 1.29 mmol) was added and the reaction was stirred for 24 h at 0 ºC.
18

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 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, t r
major = 10.8 min, t r
minor = 14.5 min). lsj 26 N-Boc protection of 20
To a mixture of compound 20 (0.38 g, 0.69 mmol) and Boc
2
O (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 %).
1
H 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). 13 C 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.
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 1
H 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 .
19

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.
DCM
DMAP
DMS
EtOAc
EtOH
MeOH
NMR
THF rt dichloromethane
4-dimethylaminopyridine dimethylsulfide
Ethylacetate
Ethanol
Methanol
Nuclear Magnetic Resonance
Tetrahydrofuran
Roomtemperature
20

9
9.1 Mechanism ozonolysis 19
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 cleavage 19
Scheme 10
The first step is a cycloaddition of OsO
4
to the double bond to form the osmate ester. This ester is hydrolyzed to the diol. This diol is then cleaved with NaIO
4
into two aldehydes.
NaIO
4
also oxidizes osmium back to its original oxidation state so the expensive and toxic osmium can be added in catalytic amounts.
21

9.3 Spectra
12
N
H
NH
2
8.0
ppm (f1)
7.0
6.0
5.0
4.0
3.0
2.0
1.0
22

15
O
O
O ppm (f1)
34
7.0
O
O
O
O
6.0
5.0
4.0
3.0
2.0
1.0
ppm (f1)
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
23

14
O
O
O ppm (f1)
23
7.0
O
O
O
O
6.0
5.0
4.0
3.0
2.0
1.0
ppm (f1)
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
24

48
HO
N
O O
N
I ppm (f1)
40
7.0
6.0
5.0
4.0
3.0
2.0
1.0
HO
N
O O
N
I ppm (f1)
7.0
6.0
5.0
4.0
3.0
2.0
1.0
25

1
BocO
N
O O
N
I ppm (f1)
7.0
6.0
5.0
4.0
3.0
2.0
1.0
26

47
O
O O
O ppm (f1)
75
7.0
6.0
5.0
4.0
3.0
2.0
1.0
ppm (f1)
150 100 50
27

70
O
O
O O
O ppm (f1)
54
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
ppm (f1)
200 150 100 50 0
28

55
N
N
H
EtO
EtO
O
I
O
8.0
ppm (f1)
56
7.0
6.0
5.0
4.0
3.0
2.0
1.0
ppm (f1)
150 100 50
29

80
N
N
Boc
EtO
EtO
O
I
O
8.0
ppm (f1)
58
7.0
+ triethylorthoformate
+ ethyl acetate
6.0
5.0
4.0
3.0
2.0
1.0
ppm (f1)
150 100 50
30

64
O O
O
O
O O
O ppm (f1)
72
7.0
6.0
5.0
4.0
3.0
2.0
1.0
ppm (f1)
150 100 50
31

1
Cox, E. D.; Cook, J. M. Chem. Rev.
1995 , 95 , 1797-1842
2
Chopra, R. N.; Gupta, J. C.; Mukherjee, B. Indian J. Med. Res.
1933 , 21 , 261
3
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 , 1949-1956
4 Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges.
1911 , 44 , 2030-2036
5
Kawate, T.; Yamada, H.; Soe, T.; Nakagawa, M. Tetrahedron: Asymmetry 1996 , 7 , 1249-
1252
6
Taylor, M. S.; Jacobson, E. N. J. Am. Chem. Soc. 2004 , 126 , 10558-10559
7
Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc.
2006 , 128 , 1086-1087
8
Gremmen, C.; Willemse, B.; Wanner, M. J.; Koomen, G.-J. Org. Lett.
2000 , 2 , 1955-1958
9 Wanner, M. J.; van der Haas, R. N. S., de Cuba, K. R.; van Maarseveen, J. H.; Hiemstra, H.
Angew. Chem. Ed.
2007 , 46 , 7485-7487
10
Sewgobind, N. V.; Wanner, M. J.; Ingemann, S.; de Gelder, R.; van Maarseveen, J. H.;
Hiemstra, H. J. Org. Chem.
2008 , 73 , 6405-6408
11
Wanner, M. J.; Boots, R. N. A.; Eradus, B.; de Gelder, R.; van Maarseveen, J. H.; Hiemstra,
H. Org. Lett.
2009 , 11 , 2579-2581
12
Krafft, M. E.; Cran, J. W. Synlett 2005 , 1263-1266
13 Macritchie, J. A.; Silcock, A.; Willis, C. L. Tetrahedron: Asymmetry 1997 , 8 , 3895-3902
14
Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett.
2004 , 6 , 3217-3219
15
Hanessian, S.; Ninkovic, S. J. Org. Chem.
1996 , 61 , 5418-5424
16 Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc.
2006 , 128 , 84-
86
17
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
19
Clayden, Greeves, Warren and Wothers, 'Organic Chemistry', Oxford University Press,
ISBN 0 19 850346 6
32