Enantioselective additions to N-stabilized carbocations
using chiral Lewis or Brønsted acids
Peter Hauwert, 0008109
Research project May 2004 - June 2005
Universiteit van Amsterdam
Van ‘t Hoff Institute for Molecular Sciences
Synthetic Organic Chemistry
Table of Contents
Content
Page number
Table of contents
1
Summary
2
List of Abbreviations
3
Chapter 1
Chapter 2
Chapter 3
Chapter 4
Introduction
1.1
General introduction
5
1.2
Reactions of N-stabilized carbocations
5
1.3
N-acyliminium ions & chiral Lewis acid catalysis
7
1.4
N-sulfenyliminion ions & chiral organocatalysis
9
Chiral Lewis acid catalysed reactions
2.1
Results
13
2.2
Discussion & conclusions
15
Chiral Brønsted acid catalysed reactions
3.1
Results
17
3.2
Discussion & conclusions
23
Summary & future prospects
4.1
Lewis acid chemistry
25
4.2
Brønsted acid chemistry
25
4.3
Nps-group and products
25
Chapter 5
Acknowledgments
Chapter 6
Experimental Part
Chapter 7
27
6.1
Lewis acid chemistry
28
6.2
Brønsted acid chemistry
33
References
Samenvatting in Nederlands
37
39
1
Summary
In this report we describe efforts towards the synthesis and application of two acidic catalysts,
in an attempt to catalyze enantioselective additions on N-stabilized carbocations.
Both have already been described in literature, but were considered promising enough to carry
on research. Furthermore, a new use is found for the amine protecting group 2nitrophenylsulfenyl (Nps), as an aid in stabilization of a carbocation. This is normally done by
Boc-, Cbz- or tosyl-groups, which require more stringent conditions for removal.
Lewis acid catalyst 4 was tried, but did not catalyze the literature reaction on which is was
tested, due to its air- and moisture-sensitive nature. Therefore, it is regarded an unpractical
catalyst for implementation in synthetic organic chemistry.
Brønsted acid catalyst 10c was synthesized in reasonable yield, and suggestions are done to
improve the yield. It was found to catalyze the reaction between Nps-protected imines and
rather reactive nucleophiles, such as indole, giving products in excellent yield, with
enantiomeric excesses up to 50%ee. One reaction was optimized, and unusual inverse
temperature effects were observed, indicating that the catalytic mechanism has features yet to
be revealed.
NO 2
N
O
O
Ti
O
F
O
O
P
OH
F
4
10c
NO2
In conclusion, catalysts of type 10c are a promising new class of acidic catalysts, combining
facile synthesis, excellent yield in catalysis and simple practical handling, as well as being
easily recoverable with full activity. However, modifications of the 3,3’-substituents will have
to be made to enhance enantioselectivity.
2
List of abbreviations
Ac
Acetyl [-C(O)CH3]
Boc
t-Butoxycarbonyl [-C(O)OC(CH3)3]
binol
1,1'-Binaphthalenyl-2,2'-diol
br (in NMR)
Broad
Cbz
Carboxybenzyloxy [-C(O)OCH2(C6H5)]
d (in NMR)
Doublet
DMSO
Dimethylsulfoxide [(H3C)2SO]
ee
Enantiomeric excess
Et
Ethyl [-CH2CH3]
EtOAc
Ethylacetate [H3CC(O)CH2CH3]
HPLC
High Performance Liquid Chromatography
iPrO
Isopropoxide [-OCH(CH3)2]
IR
Infrared spectroscopy
m (in NMR)
Multiplet
Me
Methyl [-CH3]
MeCN
Acetonitril [H3CCN]
nBu
Normal butyl [-CH2CH2CH2CH3]
NMR
Nuclear Magnetic Resonance spectroscopy
3
OTf
Trifluoromethanesulfonate [-S(O)CF3]
PE
Petroleumether, bp= 40-65°C
rt
Room temperature
s (in NMR)
Singlet
tBu
Tert-butyl [-C(CH3)3]
t (in NMR)
Triplet
THF
Tetrahydrofuran [O(CH2)4]
TLC
Thin Layer Chromatography
TMEDA
N,N,N’,N’-Tetramethyl-1,2-ethylenediamine [(H3C)2NCH2CH2N(CH3)2]
4
Chapter 1
1.1
Introduction
General introduction
Life is chiral. From the way a clam spirals, through left- or right-handedness in humans, to enzymes
and the amino acids they are composed of: it all comes down to mirror images.
Therefore, in every synthetic attempt it is very important to take into account the possibility of
forming one or more chiral centres in that molecule. In organic synthesis, the construction of certain
bonds in a target molecule can be quite challenging, even if one does not have to worry about whether
a new bond creates a stereo centre. If that becomes an issue, as it soon does when facing more difficult
molecules such as medicines or natural products, the importance of control over the stereochemistry is
obvious.
This becomes apparent soon when forming new carbon-carbon-bonds. Many of the ‘old-fashioned’
name-reactions, such as Mannich, Diels-Alder, Henry, Michael, Friedel-Crafts and Strecker reactions
are carbon-carbon-bond forming reactions. However, these generally give a racemic mixture as
product. Especially in natural product syntheses, where a multitude of subsequent steps is generally
the case, throwing away half of the product every few steps is surely not desirable
One of the challenges for the contemporary organic chemist is to make new reactions, or modify old
ones, that will give the same good yields, but with the desired product in enantiomeric or
diastereomeric excess. This can be done by using a chiral auxiliary, preferably in catalytic amounts.
Quite a few of these classic reactions have already been adapted to modern standards, or to say it
differently: including control over the stereochemistry in some way.1 This is an ever-growing field of
chemical research, and current knowledge of it has come a long way, but is also a long way from
finishing.
1.2
Reactions of N-stabilized carbocations2
Most of the above described name-reactions involve a carbocation or carbanion that is stabilized in
some way. For example, in the Henry reaction (Scheme 1A), a carbanion is stabilized by an electronwithdrawing nitro-group, giving it a lifetime long enough to attack an electrophilic carbonyl group. In
the Mannich reaction (Scheme 1B), the enol-form of an aldehyde is nucleophilic enough to react with
an imine. And in the Friedel-Crafts reactions (Scheme 1C) the charge distribution over the aromatic
group stabilizes the positively charged sp2-carbon enough to be generated at all, as a normal alkene
would not attack these electrophiles.
5
R2CH NO2
O
R2C N
O
-H
O
H2C N
O
O
R'
R' *
A: Henry reaction
OH
O
R'
R
H
N
+ NH2R'''
R''
O
R'
R
O
R''
OH NO2
R''
R''
R
R'''
R''
H
* R'
*
N
H
R'''
B: Mannich reaction
O
RHC CH2 + LG
(Lewis) acid
R'
no reaction
O
O
R
+
LG
(Lewis) acid
R'
R
O
R'
-H
R
R'
C: Friedel-Crafts acylation
Scheme 1: Henry reaction, Mannich reaction and Friedel-Crafts acylation.
One can easily understand that a stable molecule has a long lifetime, and is rather unreactive, whereas
an unstable molecule has a very short lifetime and is too reactive to be of synthetic use. And
somewhere in the middle of this ‘stability scale’ is where the interesting chemistry is found:
influencing molecules in such a manner that a small change in structure or electron density has a
substantial effect on the overall outcome of a reaction.
Stabilizing an intermediate of a reaction to a large extent leads to a species that is easily generated, but
is only slightly reactive. However, it is relatively long-lived, giving it more chance to react with a
suitable reactant. Stabilizing the intermediate only to a small extent makes it harder to generate it, but
gives a very reactive species. Perhaps even too reactive, as it could be so unstable that is reacts with
any molecule present, giving many unwanted side-reactions. So, stabilizing electrophiles and
nucleophiles is not such a straightforward task as one might think at first sight. There is a delicate
balance that must be kept in mind constantly when trying to ‘get the reaction going’.
There is a multitude of nucleophile-stabilizing groups, that are interconvertable or easily removed, but
the amount of electrophile-stabilizing groups is fairly smaller. This has resulted in many reactions
between a reactive nucleophile and a less reactive electrophile, instead of the other way around. One
of the methods to do reactions between a reactive electrophile and a not-so-reactive nucleophile is by
using a reactive N-stabilized carbocation, which enables the use of less reactive nucleophiles.
This report is divided into two parts: the first part of this report is dedicated to the use of Nacyliminium ions, described in section 1.3.1, as N-stabilized carbocation-equivalents. The research on
this subject has been done using a chiral Lewis acid.
The second part describes the use of N-sulfenyliminium ions, described in section 1.4.2, as Nstabilized carbocation-equivalents. The research on this subject has been done using a chiral Brønsted
acid.
6
1.3
N-Acyliminium ions & chiral Lewis acid catalysis
N-Acyliminium ions3
1.3.1
One of the ways of stabilizing a carbocation is to have an electron-donating group next it, such as a
tert-butyl group or an electron-rich phenyl group. Generally, these are not so easily removed; put
otherwise: they have to be present in the target molecule if one wants to use them.
Another option is using the lone pair of a heteroatom to stabilize the positive charge, preferably a
nitrogen atom, as this has many options for functionalization. If the substituents on the amine are
electron-withdrawing, the positive charge will be located mostly on carbon, whereas if the substituents
on the amine are electron-donating the positive charge will be localized mostly on nitrogen.
A classic and powerful example of this in synthesis is the use of N-acyliminium ions, depicted in
Scheme 2. Herein, an amide or carbamate 1a with a good leaving group  to the nitrogen is used.
Lewis or Brønsted acid induced leaving group departure gives the N-acyliminium ion 2a, which is
then trapped by a nucleophile, giving the product 1b. This gives the possibility to introduce various
substituents  to an amine equivalent. As the N-acyliminium ion is a very reactive intermediate, it is
possible to introduce rather unreactive nucleophiles, such as allyl- and vinylsilanes, (silyl) enol ethers,
unactivated aromatic rings and alkenes, that are difficult to introduce in other ways.
R3
O
R1
N
LG
R3

O
R1
R2
N
R3

O
R1
R2
N
Nu
R2
R1
N
Nu
2a
1a
R3
O
R2
1b
LG = e.g. -OH, -OMe, -OAc, OMs, -Cl
R1, R2 = H, alkyl or aryl
R3 = -OAlk or -OAr
Nu = e.g. allylsilanes, alkenes
(silyl) enol ethers, aryls
Scheme 2: N-acyliminium is a very active N-stabilized cation.
When using a Lewis acid to abstract the leaving group, it is often necessary for the amine to be trisubstituted, otherwise the stabilized cation could lose an amine proton to form an imine (Scheme 3); in
Brønsted acidic conditions this is however a reversible process.
H
N
R1
-LG
R2
H
N
R1
2b
LG 1 c
R3
R3
R1
N
LG
-H
R2
-LG
R2
1a
R1
N
R2
+H
R1
N
R2
3a
R1 , R2, R3 = alkyl, aryl or acyl
LG = e.g. -Cl, -Br, OMe, OAc
2a
Scheme 3: Stabilizing carbocations
These reactions have generally been induced by Lewis acids, such as BF3·OEt2, SnCl4, TiCl4 or AlCl3,
or by Brønsted acids, such as HCO2H, H2SO4/AcOH, and HCl in various solvents. It shows that this is
very powerful chemistry, but is also clear that the rest of the molecule should withstand these very
harsh conditions. Therefore it would be interesting to find ways to induce the generation of N-
7
acyliminium ions in a milder way, for example by using acids in a catalytic fashion. This becomes
even more interesting if one could use a chiral acid, as then the possibility arises of introducing
various functional groups in an enantioselective fashion.
1.3.2
Chiral Lewis acid catalysis
Lewis acids are generally used to activate carbonyls, and remove leaving groups such as alkoxy,
acyloxy, bromide and chloride. The use of Lewis acids with a chiral moiety has been around for a
couple of years4a, but these all use the Lewis acid in a stoichiometric fashion 4b, except when used for
(hetero-)Diels-Alder reactions, as these have been done with catalyst loadings ranging from 1 to 10
mol%4c. Using a Lewis acids with a chiral ligand in a catalytic fashion is rather new, and has first been
done in 2004 by Braun and co-workers, using catalyst 4
ethers and acetals 6-9
5b
5a
(Figure 1) for carbon allylation of silyl
. Also Feng and co-workers have used Ti-based Lewis acids with a chiral
ligand (Figure 1, 5) in a catalytic fashion, both in hetero-Diels-Alder reactions6a and in
cyanosilylations of aldehydes6b.
tBu
tBu
tBu
Ph
N
Ph
O
O
tBu
Ph
N
Ph
OH
TiF2
OH
+ Ti(iPrO)4
Ph
Braun's catalyst 4
Feng's catalyst 5
Figure 1: Chiral Lewis acid catalysts, devised by Braun and co-workers, and by Feng and co-workers
Using catalyst 4, Braun and co-workers have obtained products with an enantioselectivity ranging
from a modest 54%ee to an good 93%ee, depending on whether it were heteroatom-stabilized (8, 9) or
benzylic cations (6, 7), with yields ranging from a reasonable 62% up to an excellent 96% (Scheme
4)5b.
Before, chiral ligands have been used (for similar transformations), but most often always with
transition metals such as Pd as Ru as the activating moiety7. This is the first example of a catalytic,
enantioselective N-acyliminiumion reaction using a chiral Lewis acid.
8
Me
Me
OSiMe3
4 (10 mol%), CH2Cl2 , N2
96% yield, 93 %ee
SiMe3
5a
5b
Me
t
B
u
H
OSiMe3 4 (10 mol%), CH2Cl2 , N2
Me
62% yield, 80 %ee
SiMe3
6a
tBu
6b
4 (10 mol%), CH2Cl2, N2
N
Cbz
OMe
SiMe3
7a
82% yield, 56 %ee
N
O
Ph
O
Ti
4F2
Ph
N
Cbz
7b
4 , CH2Cl2, N2
O
Ph
OMe
SiMe3
8a
75% yield, 54 %ee, using 10 mol% 4 + 90 mol% TiF4
82% yield, 79 %ee, using 200 mol% 4
O
8b
Scheme 4: Carbon allylation of silyl ethers and acetals using catalyst 4 by Braun and co-workers
The aim of this part of the project is to investigate whether the results of Braun and co-workers are
more widely applicable than these few reactions. As there is room for improving the catalyzed carbon
allylation of acetals, attempts will be done to find new N-acyliminium ion precursors on which
catalyst 4 works, and if possible, improve the chiral moiety.
1.4
N-sulfenyliminium ions & chiral organocatalysis
1.4.1
N-sulfenyliminium ions
Another way of stabilizing carbocations, compared to N-acyliminium ions, is by using a sulfenyl
group on the nitrogen, instead of an acyl group (Scheme 5). A sulfenyl group is less electronwithdrawing than an acyl group, resulting in the positive charge to be slightly less localized on the C,
giving an iminium ion that is slightly less reactive. This means that one needs a more active
nucleophile, such as indole or methoxyfuran. On the other hand, as the intermediate is more stable, the
carbocation can also be generated using milder conditions. This can be advantageous if the rest of the
iminiumion precursor has more than one good leaving group, which would also be removed upon
treatment with the strong acids needed to generate N-acyliminium ions.
Another difference between N-acyliminium ions and N-sulfenyliminium ions lies in their precursors.
Whereas N-acyliminium ions are often generated by removing a leaving group  to the nitrogen, for
generating N-sulfenyliminium ions it is more convenient to protonate the imine, as these N-sulfenylN,O-acetals are not so stable and will eventually decompose to the imine anyhow.
9
R1
H
N
R1
H
R2
N
S
S
H
N
R1
R2
R2
Nu
S
S
Nu
2c
3b
H
N
R1
R2
1d
R1 = alkyl or aryl
R2 = aryl
Nu = indole, methoxyfuran
Scheme 5: N-sulfenyliminium is a rather active N-stabilized cation.
Chiral Organocatalysis 8
1.4.2
Since the beginning of catalysis, nearly always there have been metals involved, such as Pd, Pt, Rh or
Ni in so-called homogeneous catalysis, and as Lewis acids (Ti, Sn, Al), although these last ones are
not used in catalytic amounts. A lot of time has been put into mechanistic research, improving ligands,
immobilizing the catalysts and optimizing the reactions, which has made metal-based catalysis a very
successful part of chemistry. However, in modern times it is becoming increasingly important to not
only keep an eye at the atom economy, but also to inhibit the use of expensive and scarce metals.
Because these metals are so active, they can even be harmful in very small concentrations, which
makes extensive removal necessary in e.g. the food or pharmaceutical industry. Especially at an
industrial scale, the use of metals gives extra costs for removal and storage, even if catalysts are used
in ppm amounts.
Therefore, in recent years so-called organocatalysts have emerged, catalyzing reactions with yields
and stereoselectivities as good as the traditional metal-containing catalysts. And although the rate
accelerations are not as good as the traditional metal-catalyzed reactions, the appearance of these
environmentally more friendly catalysts is a growing research field. Organocatalysts are derived from
naturally occurring compounds such as L-proline, (+)-quinidine and phenylalanine, or based on
synthetically available functional groups, partly originating from ligand chemistry, such as guanidine-,
(thio)urea-, bipyridyl- or phosphane-groups. Examples of both groups are depicted in Figure 2.
t-Bu
Me
S
N
(i-Bu)2N
N
H
N
H
O
P
CO2H
N
Ph
Thiourea-based
Phenylalanine-based
Me
Ph
CO2H
N
H
(L)-Proline
OMe
Phosphane-based
NEt2
N
Ph
Ph
N
N
H
N
H
Bn
Me
Ph
MeO
HO
H
N
H
Atropisomery-based
N
(+)-Quinidine
Guanidine based
Figure 2: Examples of organocatalysts
10
Recently, Akiyama9 and co-workers, as well as Terada10 and co-workers, have reported several
catalysts 10a-f, derived from binol hydrogen phosphate, depicted in Figure 3. Using several of these
catalysts, Terada has reported enantioselectively catalyzed Aza-Friedel-Crafts alkylations with ee’s up
to 95%, and Akiyama has reported enantioselectively catalyzed Mannich-type reactions, with ee’s up
to 91 (Akiyama). Some of their results with these catalysts are shown in Scheme 6.
Using these 3,3’-bis-substituted binol hydrogen phosphates, Terada and co-workers have had the best
results with bulky aromatic substituents, such as 4-(-naphthyl)-phenyl 10d 10a or 3,5-dimesitylphenyl
10f
10b
. As they were investigating reactions of a reactive aromatic imine 11 with active nucleophiles,
e.g. methoxyfuran, they had rather easy and fast reactions, and therefore could allow with such
sterically demanding groups.
Akiyama and co-workers were investigating the electronic effects of the substituents and had the best
results with the electron-withdrawing 4-nitrophenyl group, also using an aromatic imine 13 and a
rather active silyl ketene acetal.9
a: R =
H
R
OMe
c: R =
NO2
O
O
O
b: R =
P
OH
f: R =
d: R =
R
10 a-f
e: R =
Figure 3: Several binol hydrogen phosphates used by Terada and Akiyama
11
Akiyama
HO
HO
OSiMe3
N
Ph
HN
OMe
10 c (30 mol%)
DCM
4h, 0°C
11
96% yield,
87%ee
CO2Me
Ph
12
Terada
O
O
Boc
Boc
HN
N
10 e (2 mol%)
DCM
1h, 0°C
Ph
13
O
Ph
O
HN
N
Ph
13
10 f (2 mol%)
DCM
20 h, -35°C
14
Boc
OMe
Boc
99% yield
95% ee
O
Ph
87% yield
97%ee
O
OMe
15
Scheme 6: The best results Akiyama and Terada have obtained using 3,3’-substituted binol hydrogen
phosphate catalysts
The aim of this part of the project is to investigate the scope of the bis-(4-nitrophenyl)-substituted
catalyst 10c, depicted in Figure 3. As it is a less active acid compared to Lewis acid 4, it will be tested
on reactions involving an N-sulfenyliminium ion, instead of on an N-acyliminium ion.
This catalyst was chosen as it has moderate steric properties, as well as an electron-withdrawing nitrogroup, activating the hydrogen phosphate. This activation is an important feature, as it could lead to a
broader scope of nucleophiles to be applied.
12
Chapter 2
2.1
Chiral Lewis acid catalyzed reactions
Results
2.1.1
Catalyst synthesis
As a starting point for testing Braun’s catalyst 4, the chiral ligand 19 was synthesized, starting from
the amino acid-derivative (D)-phenylglycine methyl ester hydrochloride 16, (obtained from DSM,
Geleen, The Netherlands) according to the procedure5a in Scheme 7, in an overall yield of 27% over 2
steps. This could be much higher if the first step were done with properly dried Et2O, but as the
product was obtained in sufficient amount (4 g), no attempts were done to repeat the reaction in an
improved version.
The imine-formation was improved by using a procedure by Texier-Boullet11, instead of the original
Braun-procedure which used Na2SO4 in a MeOH/CH2Cl2-mixture and was difficult to reproduce. The
new procedure consists of immobilizing the amine 17 and aldehyde 18 on basic alumina and mixing
these. After 72 h the product 19 was released from the alumina in quantitative yield by extraction with
CH2Cl2, and excess aldehyde was removed by column chromatography. If the reaction is performed
using exactly 1 equivalent of both reactants, the reaction is complete after 72 h and no purification is
necessary. However, if there is a slight excess of either of the reactant, column chromatography is a
necessity, and a reaction time of 24 h can be used, giving the product in approximately 96% yield.
tBu
tBu
18
Ph
Ph
NH2.HCl
PhMgBr, N2
MeO
O
Et2O
16
27% (lit. 66%)
Ph
NH2
OH
Ph 17
tBu
tBu
O
Ph
N
Ph
OH
OH
basic alumina
99%
Ph
OH
19
Scheme 7: Preparing the ligand 19
Once the ligand 19 was obtained, this was reacted with a half equivalent of Ti(iPrO)4 (Scheme 8),
forming titanium-ligand-dimers 20, a stable, storage-type precursor of the active catalyst5a.
Afterwards, this was reacted with TiF4, which should give the active TiIVF2-ligand-complex 4. As this
compound is an extremely moisture- and air-sensitive compound, we were not able to get a sample of
this compound in a deuterated solvent in an NMR-tube, without risking the possibility of reaction with
moisture or air. Therefore, characterization of this complex was attempted by directly using it as a
catalyst.
13
tBu
Ti(iPrO)4, N2
19
Ti(19)2
CH2Cl2
tBu
TiF4, Ar(g)
CH2Cl2/CH3CN
90%
92%
Ph
N
Ph
O
20
O
TiF 2
4
Ph
Scheme 8: Preparing the Lewis acid catalyst 4
2.1.2
Substrate synthesis
The reaction on which catalyst 4 would be tested was a literature reaction by Braun5b, between
allyltrimethylsilane and the N-acyliminium ion precursor N-Cbz-protected 2-methoxypiperidine 23b,
of which the synthesis is described in Scheme 9.12,13,14
The substrate synthesis was performed via two routes, both starting from N-Cbz-protected valerolactam 22, either in a two-step one-pot fashion13 or in two separate steps14.
The one-pot procedure starts with reduction of 22 by NaBH4 in MeOH, followed by addition of 2M
H2SO4 in MeOH to yield the N,O-acetal 23b in 54%.
The second method starts with reduction of 22 by LiEt3BH followed by an oxidative workup to give
the hemi-acetal 23a in 73%, which was subsequently treated with Sc(OTf)3 in CH2Cl2/MeOH, giving
the N,O-acetal 23b in 28% over two steps.
At first, this sequence was the preferred, but both steps were difficult to reproduce from literature14
after which the one-pot procedure was found and applied, giving the substrate for catalysis in
reasonable yield.
1) nBuLi, THF, N2
N
H
21
O 2) CbzCl
65%
1) NaBH4, MeOH
N
Cbz
O
54%
(two-step one-pot)
2) 2M H2SO4, MeOH
N
Cbz
OMe
23 b
22
28% over 2 steps
Sc(OTf)3 (1%mol)
1) LiEt3BH, THF, -78°C
2) 30% aq, H2O2
73%
N
Cbz
OH CH2Cl2/MeOH
23 a
38%
Scheme 9: Substrate for the Lewis acid catalyst
14
2.1.3
Catalysis
The reaction in which catalyst 4 was tested is depicted in Scheme 10, but this only gave eliminated
product 23c, even when a large excess (10 eq) of nucleophile was used. The desired product 24 was
obtained using BF3•OEt2 as Lewis acid in stoichiometric amounts, but this product was of course
racemic (Scheme 11).
Using the catalyst in stoichiometric amounts was not possible as there was not enough available.
Varying the catalyst loading (10 or 20 mol%), the amount of nucleophile (1.2, 2 or 10 eq), the reaction
time (from 18-60 h) and the warm-up time (from 6-22 h) were not enough to avoid getting only
eliminated product 23c. The catalyst has also been made in situ, prior to addition of the substrate 23b,
but this also did not result in the desired product, and every time only eliminated product 23c, starting
material and free ligand 19 were recovered.
1) 4 (10-20 mol%), CH2Cl2 , -78°C
N
Cbz
TMS
OMe 2)
N
Cbz
N
Cbz

N
Cbz
Ti(19*)F2 OMe
24
23 b
N
Cbz
Scheme 10: Testing catalyst 4
1)
N
Cbz
TMS, CH CN
3
OMe 2) BF3.OEt2, 0°C
23 b
73%
N
Cbz
24
Scheme 11: The BF3•OEt2 -catalysed N-acyliminium ion reaction
As this is a literature reaction that should give product 24 in 82% yield and 56%ee5b, this could mean
that a) the catalyst was not formed, or b) was deactivated by water or oxygen, as Ti IV-complexes are
known to be very moisture-sensitive.
2.2
Discussion and conclusions
To exclude air or water from entering the reaction vessel, the reactions (both making the catalyst and
doing the catalysis) were carried out according to procedures described by Braun 5c, meaning ovendried glasssware, under an argon atmosphere, using distilled solvents and reactants from a fresh bottle,
adding the reactants using a syringe or via cannula and using Schlenk techniques. The instable nature
of the catalyst made it very difficult to characterize it by spectroscopic means.
15
The aim of this part of the project was to investigate the scope of catalyst 4 and whether it could be
widely applicable. Because the catalyst has to be generated for every reaction in a very timeconsuming manner, and because it requires handling extremely air- and moisture-sensitive
compounds, it was considered unpractical, and further research was ceased.
Despite the difficulties in preparing the last step of the Lewis acid catalyst, making the ligand 19
however is an easy task, of which the imine-formation was improved. This gives a source of chirality
that could be used as a basis for other catalysts, based on less air- and moisture-sensitive activating
centers.
It should be noted that in the hands of Braun and co-workers this reaction gave only 82% yield and
56%ee. It gave better results (62-96% yield, 90-93% yield) for phenyl-stabilized cations, but the Nstabilized as well as the O-stabilized cations gave poor results anyhow.
16
Chapter 3
3.1
Chiral Brønsted acid catalyzed reactions
Results
3.1.1
Catalyst Synthesis
Akiyama’s p-nitrophenyl substituted binol hydrogen phosphate catalyst 10c was synthesized using a
procedure based on work by Wipf15, Jørgensen16, and Akiyama9, which is described in Scheme 12.
The original article did not contain an experimental part, therefore this procedure was devised,
although afterwards we received Akiyama’s procedure. 17
B(OH)2
1) nBuLi, TMEDA, Et2O, N2
OMe 2) B(OEt)3
3) 6M HCl
OMe
OMe
B(OH)2
OMe
+
OMe
+ starting material
OMe
B(OH)2
25
34%
26 a
33% 26 b
33%
NO2
NO2
B(OH)2
OMe
OMe
1) 4-NO2-PhBr, Ba(OH)2,
Pd(PPh3)4 (20 mol%), Ar(g)
degassed dioxane/H2 O
2) BBr3, DCM
OH
OH
1) POCl3,
pyridine
2) H2O
3) 6M HCl
O
O
O
P
OH
30%
86%
B(OH)2
26 a
27
10c
NO2
NO2
Scheme 12: Making the Brønsted acid catalyst
The literature yields of the first reaction were 87% (Jørgensen)16 and 71% (Wipf)15. Both times the
reaction was done their conditions were exactly followed. The obtained products were 26a, monoborated product 26b, and starting material, meaning that the deprotonation was not sufficient. This is
probably because the Et2O was not sufficiently dried.
The Suzuki coupling proceeded smoothly, giving the product in a slighly higher yield than reported in
literature17 (86% vs 82%), although more Pd(PPh3)4 was used (20% vs 7 %).
As for the low yield of the last step, this is mostly because of the work-up procedure from Akiyama9,
which is stated in the Experimental section and makes recovery of pure catalyst very difficult. The
crude yield is a satisfactory 89%, but obtaining a solvent-free catalyst in good yield is hardly possible.
After finishing the practical work another work-up procedure by Terada10 was found, which makes
this easier. However, it must be added that in Terada’s work the 3,3’-substituents are nonfunctionalized aryl groups. The presence of a polar nitrophenyl-group at that position could influence
17
the yield and ease of this procedure. This new procedure is also stated in the Experimental section,
although it was not used for this project.
3.1.2
Catalysis: Enantioselective Aza-Friedel-Crafts alkylation of indole
3.1.2.1
Reaction optimization
Before using catalyst 10c on the N-acyliminium ion substrate 23b, commercially available
unsubstituted binol hydrogen phosphate 10a (Figure 4) was tested on the N-acyliminium ion precursor
23b. Because only eliminated product 23c was obtained, binol hydrogen phosphates as catalysts for
this substrate were deemed not active enough, as expected.
R
H
a: R =
O
O
c: R =
P
O
NO2
OH
d: R =
R
10
Figure 4: The investigated binol hydrogen phosphate catalysts
Therefore, we decided to use an N-sulfenyl protected imine, developed in our group18, instead of an Ncarbamate-protected N,O-acetal. The sulfenyl protecting group used was nitrophenylsulfenyl (Nps), a
well-known protecting group in peptide chemistry, which is known to be easily removed in many
ways, for example by acidic hydrolysis or use of nucleophiles.19 This substrate was made from the
methyl hemiacetal of methyl glyoxylate 28 and (ortho-nitrophenyl)sulfenylamine 29, as depicted in
Scheme 9.
O2N
O2N
Cl
NH3 (25% in H2O)
S
28
H2N
Na2SO4,
S
THF, MeOH
30
88%
O
MeO2C
.
MeO2C MeOH
CH2Cl2
29
85%
O2N
MeO2C
N
=
S
N
Nps
31
Scheme 9: Substrate for the Brønsted catalyst
With the substrate in hand, unsubstituted catalyst 10a was first tested on the reaction between the Nprotected imine 31 and indole 32 (Scheme 10), and as this gave the expected product 33,
p-nitrophenyl-substituted catalyst 10c was tested. Using a catalyst loading of only 2 mol%, the product
was obtained in quantitative yield after 3 h and with a promising enantiomeric excess of 30%ee. The
reactions require no special precautions, such as working moisture- or air-free, and are easily
monitored using TLC and chiral HPLC. In this case removing the Nps-group off the addition product
33 would result in a protected -amino acid, with the nucleophile also on the -position.
18
MeO2C
CO2Me
+
32
N
H
N
H
NH
2 mol% 10 a/c
Nps
Nps
CH2Cl2
31
92-99% isolated yield
10a: 20 %ee
10c: 30 %ee
N
H
33
Scheme 10: Aza-Friedel-Crafts reaction with binol hydrogen phosphate catalysts
A first reaction with 30%ee is an encouraging result, but not a satisfactory one. Therefore, solvent and
temperature were varied, while keeping the catalyst loading constant at 2 mol%, the results of which
are depicted in Tables 1 (solvent) and 2 (temperature).
Table 1: Solvent effects in the Aza-Friedel-Crafts reaction, using catalyst 10c
Solvent
Polarity a
%ee Time (h)
Toluene
2.3
25
24
CH2Cl2
3.4
30
3
(CH2Cl)2
3.7
30
3
CHCl3
3.9
45
3
MeCN
6.2
5
24
DMSO
6.5
0
96
a: Snyder polarity index20
As can be seen in Table 1, the more polar a solvent is used, the better the enantioselectivity becomes.
So going from toluene to CH2Cl2 to CHCl3, the enantioselectivity increases from 25%ee to 30%ee to
45%ee. More polar solvents are always either hydrogen bond donors or acceptors. MeCN and DMSO
were tried but these give hardly any enantioselectivity. This is probably because in those cases the
solvent either competes with the substrate for protons from the catalyst (and of course wins), and/or
disturbs the complexation of the catalyst with the protonated imine, thereby giving lower ee’s.
Ethereal solvents such as diethylether or THF were not tried as they are known to have the same
problem as DMSO or MeCN10b. Also protic solvents will not work, as they will compete with (and
again win from) the catalyst for donating protons to the substrate, giving racemic product. Therefore,
the best solvent for this system is chloroform.
As for the temperature (Table 2), it was found that lowering the reaction temperature resulted in lower
ee’s. Normally, lowering the temperature increases the enantioselectivity21,10b, because the ionic
interactions between the catalyst and the (protonated) substrate are generally longer-lived, thereby
giving more chance to ‘transfer’ the chiral information from catalyst to substrate. There are cases
known where there is an inversion temperature22 above and below which the enantioselectivity drops,
but this is by far not general, and almost only observed in addition of alkylzinc reagents to
aldehydes.23
19
As lowering the temperature did not give the desired result, the temperature was raised, using both
CHCl3 and (CH2Cl)2 as solvents. In (CH2Cl)2, at 50°C the observed enantioselectivity was indeed a bit
higher, but at 80°C the enantioselectivity was again only 30%ee. In refluxing CHCl 3 (62°C), the
enantioselectivity was just a few percent higher than at room temperature. Lowering the temperature in
CHCl3 was not tried, but as this did not have the desired effect in the fairly similar CH2Cl2, the chance
that this would work is rather small.
Table 2: Temperature effects in the Aza-Friedel-Crafts reaction, using catalyst 10c
Solvent
Temperature (°C)
%ee
Time (h) a
-78
16
24
-25
24
7
20
30
3
20
30
3
50
34
1.5
80
30
1
20
45
3
62
50
3
CH2Cl2
(CH2Cl)2
CHCl3
a: 92-99% yield
These observations probably indicate that there are two mechanisms, or one mechanism with two
different rate-determining steps. Further investigations possibly clarify this, but that is not yet relevant,
as the enantioselectivity for this system is still not sufficient.
To conclude, the ee for this system (reaction between imine 31 and indole 32 with 2 mol% of catalyst
10c) cannot be raised above 50%ee.
3.1.2.2
Catalyst comparison
These reactions have also been done with two similar catalysts18: the unsubstituted binol hydrogen
phosphate 10a and the 3,3’-bis(4-biphenyl)-binol hydrogen phosphate 10d.
The results of these reactions, compared to the p-nitrophenyl catalyst 10c are shown in Table 3.
Table 3: comparing catalysts, Aza-Friedel-Crafts reactiona)
CH2Cl2, 20°C
CH2Cl2, -25°C
Toluene, 20°C
CHCl3, 20°C
% ee
Time (h)
% ee
Time (h)
% ee
Time (h)
% ee
Time (h)
10a
20
1
24
18
26
24
31
2
10d
67
48 a)
no reaction
65
72 b)
74
120
10c
30
3
25
24
45
0.5
24
7
a) 70% conversion, b) 40% conversion
20
In all of the cases studied, the 4-nitrophenyl-substituted catalyst 10c is as good as, or better than, the
unsubstituted binol hydrogen phosphate 10a. 10a is faster than 10c at room temperature, but at lower
temperatures this is not the case any more. The biphenyl-substituted catalyst 10d generally gives
higher enantioselectivity than the other two catalysts, but the problem is that it is not reactive enough
to give an acceptable conversion, even after several days.
3.1.2.3
Further investigations
Lowering the catalyst loading was tried only once, using 0.2 mol% of catalyst 10c in refluxing CHCl3
and this gave the same results as using a catalyst loading of 2 mol%, namely 92% yield and 50%ee
after 3 h. Lowering the catalyst loading even further could thus be possible without losing
enantioselectivity, but in that case the reaction time would become rather long. A phenomenom that
was noticed only when we used such a low catalyst loading, is that the reaction speed went down
drastically as the reaction progressed. This is probably due to catalyst inhibition by the product, as this
is more basic than the starting material imine.
The reaction was also tried once with a catalyst loading of 10 mol%, but this gave no increase in
enantioselectivity.
To investigate whether the catalyst really influences the reaction, and not just deracemizes the product
via dynamic kinetic asymmetric induction (mechanism in the top part of Scheme 10, stereochemistry is
assigned by X-ray crystallography of enantiopure crystals18), more tests were done to check the
stability of the product under acidic and basic conditions.
First, the product stability under the reaction conditions was tested, by stirring racemic product
(obtained from the reaction of indole and substrate 31 with racemic 10a) with 5 mol% of catalyst 10c
in CH2Cl2. This reaction was followed on chiral HPLC, and after 96 h the reaction mixture was still
racemic. Thus, the product is stable under the reaction conditions, meaning the catalyst truly
influences the reaction.
Furthermore, the product (with ee of 26%) was treated with a 10-fold excess of NEt3, to check the
stability of the product under basic conditions, as this had been used to quench the reaction. Also here,
no change in ee was observed after 24 h, implying that the product and its stereochemistry are stable
under both acidic and basic conditions.
21
OMe
cat*-H
bulk
OMe
H
H
H
O
O
NRH
OMe
O
O
O
*
NH
H
NRH
NRH
NRH
O
O
bulk
NH
H
MeO2C
P
H
NH
NH
racemic
racemic
achiral substrate in chiral environment
Enantio-enriched
Chiral acid-induced deracemization
OMe
OMe
H
O
*
base
O
H-base
CO2Me
NRH
NRH
NH
NRH
NH
N
H
achiral
Enantio-enriched
racemic
Base-catalyzed racemization
Scheme 10: Possible mechanism of acid-induced deracemization, and of base-induced racemization
3.1.3
Catalysis: Enantioselective Pictet-Spengler condensation
As catalyst 10c has proven active in enantioselectively catalyzing the Aza-Friedel-Crafts reaction, it
was also tested on the Pictet-Spengler condensation of Nps-protected tryptamine 35 (made by reacting
tryptamine with Nps-Cl 30) and hexanal 36, which is depicted in Scheme 11.
C5 H11
HN
N
H
Nps
O
36
2 mol% 10
Na2SO4
CHCl3
N
Nps
-H
*
N
H
C5H11
37
N
H
N
Nps
C5H11
35
Scheme 11: Pictet-Spengler condensation with binol hydrogen phosphate catalysts
This reaction had previously been done18 with the unsubstituted and biphenyl-substituted catalysts 10a
and 10d, but the 10d was too slow to be of practical use, and 10a gave no higher enantioselectivity
than 17%ee. The results of catalyst 10c, as well as the results of catalysts 10a and 10d, are shown in
Table 4. This shows that catalyst 10c is indeed faster than the biphenyl-substituted catalyst 10d, but
with enough steric bulk to give more enantioselectivity than the unsubstituted catalyst 10a. However,
the ee’s are still not high enough to be of practical use.
Although the optimal temperature for this reaction is much lower than in the Aza-Friedel-Crafts
reaction, lowering the temperature even more results in a decrease of enantioselectivity. This could
mean that the same change in rate-limiting step takes place as in the case of the Aza-Friedel-Crafts
reaction, or that the preferred mode of binding of the protonated imine to the catalyst is different at
different temperatures. It could be worthwhile to find the optimum temperature between 25°C and 78°C, but the chance that the enantioselectivity will be high (>95%ee) is negligible.
22
Table 4: Comparing catalysts, Pictet-Spengler condensation
T (°C)
%ee, obtained with catalysts 10a, 10c, and 10d
10a
10d
10c
a)
5
22
12
-18 a)
8
18
24
-78 b)
17
No reaction
16
20
a) in CHCl3, b) in CHCl3/CH2Cl2=2/1
3.2
Discussion and conclusions
The Brønsted acid catalyst 10c as described by Akiyama was synthesized and the scope of its
reactivity was tested on an Aza-Friedel-Crafts reaction and a Pictet-Spengler condensation.
The catalyzed Aza-Friedel-Crafts-reaction between imine 31 and indole 32 was optimized in both
solvent and temperature. The best solvent for this system was found to be CHCl 3, the most polar
commonly used solvent that is neither a proton-donor nor a proton acceptor. Using a catalyst loading
of 2 mol%, this reaction was completed in 3 h at rt, giving the product in 95% isolated yield and in
45%ee.
Lowering the temperature resulted in a decrease of enantioselectivity, something uncommon when
concerning ionic interactions between catalyst and substrate. Normally the enantioselectivity increases
when lowering the temperature, as the interactions between catalyst and substrate are generally longerlived. This possibly means that the mode of binding between substrate and catalyst is not the same at
all temperatures, or that the rate-limiting step is not the same at all temperatures.
For (CH2Cl)2, raising the temperature from 25°C to 50°C resulted in an increase from 30%ee to
34%ee. Raising the temperature further to 80°C gave an enantioselectivity of again 30%ee, so the
optimal temperature should be around 50-55°C. For CHCl3, raising the temperature to 60°C did not
result in a significant rise in enantioselectivity.
Lowering the catalyst loading did not impair the enantioselectivity, although the reaction rate
decreased, and the problem of catalyst inhibition by the product was noticed. Using 0.2 mol% of
catalyst still resulted in 92% yield, but lowering the catalyst loading even more is not recommended. A
higher catalyst loading of 10 mol% did also not give higher ee’s.
In the catalyzed Pictet-Spengler condensation between Nps-protected tryptamine 35 and hexanal 36,
catalyst 10c proved to be as good as, or better than, similar catalysts 10a or 10d. The highest
enantioselectivity obtained was 24%, in a reaction in CHCl3 at -18°C, using a catalyst loading of 2
mol%, giving the product in 95% isolated yield after 4 h.
23
To conclude, 3,3’-bis-substituted binol hydrogen phosphates are a promising source of chiral acidic
catalysts. 4-Nitrophenyl as substituent activates the catalyst sufficiently to make it fast enough,
although ee’s did not become high enough to be of practical use (>95%ee). Further variation of the
substituents on the binol part is required to obtain sufficient enantioselectivity. One could think of
using the more reactive 3,5-dinitrophenyl- or 3,5-di(trifluoromethyl)phenyl-groups as substituents,
giving catalysts 10g and 10h. As the sluggish biphenyl-substituted catalyst 10d has given the highest
ee’s up to now (74%ee, table 3) , a CF3-activated form of the biphenyl substituted catalyst, 10i, could
combine the steric bulk of the biphenyl-group with the activating properties of nitro- or trifluoromethyl-groups (Figure 5). In these cases CF3 is advised instead of NO2 because it has better solubility
properties.
NO2
CF3
R
O
O
O
h
g
P
NO2
OH
CF3
CF3
R
10 g-i
i
CF3
Figure 5: Possibilities for further research towards binol hydrogen phosphate catalysts
Although the enantioselectivity is not yet enough to be of practical or industrial use, a further thing to
emphasize is the practical simplicity of these reactions: the bench-stable catalyst and the reactants are
dissolved under an aerobic atmosphere, taking no precautions to exclude water. The mixture is then
stirred until the reaction is completed, which is monitored by either TLC or chiral HPLC. Only PictetSpengler reactions taking longer than one hour were performed under N2 to avoid oxidation of the
aldehyde to the corresponding carboxylic acid, which would probably also catalyze the reaction, but
not enantioselectively.
After diluting the reaction mixture with petroleum ether to decrease the polarity, this crude reaction
mixture is purified with flash chromatography, to remove the catalyst and excess indole or aldehyde. It
should be noted that both reactions are very clean, and no byproducts are observed. There is however
approximately 5% loss of product on the column, decreasing the isolated yield.
When the product and excess indole or aldehyde have eluted, the catalyst is still at the top of the
column. Addition of 2% acetic acid to the eluent system flushes out the catalyst, which after
evaporation of solvents has full activity.
This recovered catalyst was tested on the Aza-Friedel-Crafts reaction and found to give the same
yields and ee-values as the freshly prepared catalyst. This means that this type of catalyst is indeed
easily recoverable and reusable, giving these catalysts an extra advantage.
24
Chapter 4
4.1
Summary and future prospects
Lewis Acid chemistry
The Lewis acid catalyst 4 as described by Braun was not obtained or possibly deactivated directly after
synthesis, as it did not catalyze a literature reaction.
This is probably because of the instable nature of this class of compounds, implying that it could only
be used as a catalyst by those having experience in handling very instable compounds. It is thus a nice
attempt towards an enantioselective catalyst, but definitively not one of choice for a synthetic organic
chemist.
Despite the difficulties in preparing the last step of the Lewis acid catalyst, making the ligand 19
however is an easy task, giving a source of chirality that could be used as a basis for other catalysts,
based on less air- and moisture-sensitive activating centers.
4.2
Brønsted acid chemistry
The Brønsted acid catalyst 10c, as described by Akiyama, was obtained, and the scope of its reactivity
was tested on an Aza-Friedel-Crafts reaction and a Pictet-Spengler condensation, both using Nsulfenyl-protected substrates.
The Aza-Friedel-Crafts reaction was optimized in both solvent and temperature. CHCl 3 gave the best
results for this catalyst, being the most polar commonly used solvent that is neither a hydrogen-donor
nor a hydrogen-acceptor. The highest enantioselectivity obtained was 50%ee, using CHCl3 at 50°C.
Lowering the temperature did not give higher ee’s, so with this catalyst this is probably the highest
obtainable enantioselectivity.
Catalyst 10c could be easily recovered by flash chromatography, after which the activity was
unchanged, meaning that the catalyst is truly recoverable and reusable, which is always a nice feature
for a catalyst.
4.3
Nps-group and products
2-Nitrophenylsulfenyl (Nps) is known to be a good amine protecing group in peptide chemistry, which
is fairly easily attached (using the sulfenylchloride) and removed in various ways (e.g. acidic
hydrolysis, nucleophiles)19. In this research it has also proven to be a good group for aiding in
stabilizing a carbocation, creating an N-sulfenyliminium ion, instead of the more commonly used Nacyliminium ion.3 The o-nitro-group gives the Nps-group the proper electron-withdrawing properties
to balance easy attachment and easy removal.18, 19
25
The products of the Aza-Friedel-Crafts-reactions are protected -amino acids. If the catalyst activity
would be improved, other nucleophiles could be used, giving a new entry into non-natural amino
acids, an interesting topic of research.
Furthermore, it should be noted that indole, tryptamine and their derivatives are abundantly found in a
variety of naturally occurring compounds, as well as synthetic derivatives of these, that exhibit
physiological properties (Figure 6).
(+)-Lysergic acid diethylamide (better known as the party drug LSD) is derived from natural (+)Lysergic acid and has hallucinogenic activity. Keramamine C is the metabolic precursor for a natural
product from an Okinawan marine sponge of the genus Haliclona and has anti-bacterial activity24.
Eudistomin C comes from the Caribbean tunicate Eudistoma Olivaceum, and has anti-viral activity,
for example against Herpes Simplex Virus type I.25
O
N
N
Br
H
N
HO
O

Eudistomin C
anti-viral activity H2N
NH
S
(+)-Lysergic Acid Diethylamide (LSD)
CNS-activity
NH

NH
N
Keramamine C
anti-bacterial activity
Figure 6: Naturally occurring tryptophan derivatives
26
Chapter 5 Acknowledgments
Prof. Henk Hiemstra and dr. Jan H. van Maarseveen are acknowledged for giving me the opportunity
to do this research in their group, as well as for encouraging me and for acquiring the original
Akiyama-procedure (in English).
Martin Wanner and Martin Berkheij are gratefully acknowledged for practical help and daily
guidance. Furthermore, Martin Wanner is thanked for the work on the Pictet-Spengler reactions and
the Aza-Friedel-Crafts reactions with the unsubstituted and the biphenyl-substituted catalysts 10a and
10d, donation of indole 31, and the crystal structure and specific rotation of Aza-Friedel-Crafts
product 33.
Han Peeters is acknowledged for the mass spectrometry measurements, Jan Geenevasen & Lidy van
der Berg for help with NMR-spectroscopy, and Prof. Hans E. Schoemaker from DSM-Geleen is
acknowledged for the generous donation of the D-phenylglycine methylester hydrochloride 16, the
starting material for the Lewis acid ligand 19.
Furthermore, I would like to thank my labmates Stefan Warsink, Remko Detz, Dennis den Boer and
Martin Berkheij, who added a good social factor to my research and made this year even more fun.
These thanks also go out to the rest of the Organic Synthesis group.
27
Chapter 6 Experimental Section
General Methods
Commercially available solids were employed without further purification unless otherwise stated.
CDCl3 was dried with molecular sieves (4 Å) and kept over beaten silver. CH2Cl2 and MeCN were
distilled from P2O5 and then CaH2. THF and ether were distilled over sodium/benzophenone.
BF3•OEt2, TMEDA, dioxane and petroleum ether 40-65°C were distilled before use.
Specific rotations were measured on a Perkin-Elmer 241 polarimeter. If no literature values are stated
they are either unavailable or exactly the same. Melting points were measured on a Wagner & Muntz
Polytherm A melting point microscope. IR-spectra were collected on a Bruker IFS 28. NMR-spectra
were collected on a Varian Inova 500 and a Bruker Avance 400, in CDCl 3 solutions, unless otherwise
stated. HPLC was done using a Merck Hitachi L6200 with a chiral OD column. Eluent systems were
heptane/isopropanol=75/25 for the Aza-Friedel-Crafts products, and heptane/isopropanol=90/10 for
the Pictet-Spengler products. When the reaction mixture was sampled for HPLC, it was first filtered
over a short path of basic alumina to remove the chiral catalyst, flushing this with EtOAc. TLC was
done using precoated silica gel Merck 60 F254, and columns were packed with Biosolve silica gel 60 Å,
0.032-0.063 mm, 230-480 mesh. D-Phenylglycine methyl ester hydrochloride (16) was generously
donated by DSM, Geleen, The Netherlands.
6.1
Lewis acid chemistry
(R)-2-Amino-1,1,2-triphenylethanol (17) was prepared according to a procedure by Braun et al.5a:
Ph
NH2
A three-necked flask was equipped with a pressure-equalizing dropping funnel closed
by a septum, a coil condenser connected to the combined N2/vacuum line, and a
Ph
OH
Ph
stopper. The flask was charged with magnesium cuttings (12.1 g, 498 mmol), and the
air was replaced by N2. Absolute diethyl ether (17 ml) was added through the dropping funnel and the
stopper was removed for the addition of crystalline iodine (approx. 10 mg). The flask was closed
immediately and the mixture was stirred until the brownish color disappeared. Thereafter, neat
bromobenzene (13 ml, 123 mmol) was added and the mixture was warmed with a heat gun without
stirring. After the start of the reaction, a solution of bromobenzene (53 ml, 504 mmol) in 86 ml of
diethyl ether was added through the dropping funnel within 3 h, in course of that the mixture boiled
gently without external heating. After stirring for an additional 3 h at room temp., the mixture was
cooled to 0°C and (R)-16 (10.0 g, 47.4 mmol) was added in small portions at such a rate that the
temperature did not exceed 5°C. After stirring for 20 h at rt, the reaction mixture was slowly poured
into a beaker containing 400 g of ice. The mixture was treated with 500 ml of 6 M hydrochloric acid
and stirred vigorously. The hydrochloride of (R)-17 formed thereby as a white precipitate was
collected in a suction filter, washed with diethyl ether and dissolved in a 1 M solution of sodium
hydroxide in methanol. The solution was concentrated and the oily residue was distributed between
28
dichloromethane (350 ml) and water (175 ml). The aqueous phase was removed and the organic layer
was washed three times with 85 ml of water, dried with MgSO4, after which solvent was removed
under reduced pressure to give the product in 60% yield as a white solid. This was recrystallized from
toluene to give 3.8 g (8.6 mmol) of product in 27% yield (lit.66%)5a.
[]D20= +227° (c=1 in CHCl3, lit.5a: [D=+235°); mp= 125-125°C (lit.5a: 131-133°C) – IR: 3400,
3100, 3080, 3040, 1600, 1580, 1500, 1450, 1180, 920, 750, 740, 705 cm-1 - 1H NMR:  1.56 (br. s, 2
H), 4.70 (br. s, 1 H), 4.97 (s, 1 H), 6.97-7.40 (m, 13 H), 7.71-7.74 (m, 2 H) – 13C-NMR (100MHz): 
61.6, 79.4, 125.9, 126.1, 126.4, 126.9-127.1-127.3, 128.4-128.6, 139.9, 143.8, 146.4. This is correct
according to literature
5a
. The lower melting point is probably because it was a glass, instead of
crystals.
(R)-2,4-Bis-(1,1,dimethylethyl)-6-{[(2-hydroxy-1,2,2-triphenylethyl)imino] methyl} phenol (19) was
prepared according to a procedure described by Texier-Boullet11:
tBu
3,4-bis-(1,1-dimethylethyl)-2-hydroxybenzaldehyde 18 (40.2 mg; 0.174
mmol) was stirred with chromatographic alumina (50 mg; Fluka 5016A,
pH=9.5). A mixture of 17 (50.2 mg; 0.172 mmol) dispersed on alumina (50
tBu
Ph
N
Ph
mg) is slowly added to the aldehyde dispersed on alumina. After 72 h the
OH
product is extracted with dichloromethane (2x5 ml) and the solvent is
OH
removed under reduced pressure, after which 86 mg (0.17 mmol) of pure
Ph
product is obtained in 96-99% yield as a yellow solid. D = +182° (c=1.0; lit.5a: D=+187°, c=1.0);
mp= 129-130°C (lit.5a: 129.5-130.5°C)– IR: 3565, 3061, 3030, 2959, 2867, 1625 cm-1 - 1H-NMR: 
1.25 (s, 9H), 1.39 (s, 9H), 3.18 (br s, 1H), 5.47 (s, 1H), 6.96 (d, 1H, J=2.3 Hz), 7.07-7.37 (m, 14H),
7.61 (d, 2H, J=7.7 Hz), 8.39 (s, 1H), 11.64 (s, 1H) –
13
C-NMR (100MHz): 29.2, 31.3, 34.0, 34.9,
80.3, 117.8, 126.2, 126.3-126.5, 126.9-127.0, 127.2, 127.4, 127.5-127.6, 128.0, 129.5, 136.5, 138.7,
140.1, 143.7, 144.9, 157.6, 168.4. This is correct according to literature 5a.
[OC-6-22’-(A), (R), (R)] -Bis- {2,4-bis-(1,1,dimethylethyl)-6-{[(2-hydroxy-1,2,2-triphenylethyl)imino]
methyl }-phenolato(2-)-N,O,O’}-titanium (20) was prepared as described by Braun et al.5a :
tBu
A Schlenk vessel equipped with a magnetic stirrer, a reflux condenser
with a connection to the combined argon/vacuum-line, and a septum,
was charged with the ligand 19 (150 mg; 0.297 mmol). The air in the
tBu
Ph
N
O
flask was replaced by N2, and absolute dichloromethane (2 ml) was
Ph
Ph
O
Ti
O
Ph
added. Titanium tetraisopropoxide (40 l, 0.145 mmol) was injected,
Ph
and the solution was heated to reflux for 4 h.
Ph
O
tBu
N
The solvent was removed in a rotary evaporator and the solid residue
was crystallized in MeOH/CHCl3 (2/1), to give 141 mg (0.13 mmol) of
tBu
product in 92% yield as yellow crystals (lit. 98% yield). []D25: +314°
(c=0.71 in CHCl3; lit.: D=+287°, c = 0.74 in CHCl3); mp= 280-281°C (lit.5a: 279.5-281°C) – IR:
29
3060, 3025, 2960, 2870, 1620, 1540, 1310, 1255, 1175, 1030, 850, 760, 700 cm-1; 1H-NMR:  0.55 (s,
18 H), 1.24 (s, 18 H), 6.45 (s, 2 H), 6.94-6.99 (m, 12 H), 7.05 (d, 2H, J=2.5 Hz), 7.10-7.12 (m, 6 H),
7.22 (d, 2 H, J=2.5 Hz), 7.50-7.60 (m, 12 H), 8.42 (s, 2 H) – 13C-NMR (100MHz): 28.5, 29.7, 31.2,
33.9, 34.3, 88.8, 92.9, 121.0, 125.5, 126.1, 126.4, 126.7, 127.0, 127.3, 127.7, 127.9, 128.5, 130.2130.4, 136.7, 138.9, 140.4, 147.3, 147.3, 162.6, 164.6. This is correct according to literature 5a. On a
400 mg-scale the yield dropped to 85%.
(R)-Difluoro - {2,4-bis-(1,1,dimethylethyl)-6-{[(2-hydroxy-1,2,2-triphenylethyl)imino]methyl}phenolato (2-)-N,O,O’}-titanium (4) was prepared as described by Braun et al.5a :
tBu
A 10-ml flask, equipped with a magnetic stirrer and a connection to the
combined argon/vacuum line, was charged with 20 (142 mg, 0.134 mmol) and
tBu
Ph
N
Ph
O
closed with a septum. The air in the flask was replaced by argon, and absolute
O
dichloromethane (4.5 ml) was injected by syringe. In a second flask, titanium
TiF 2
tetrafluoride (17.0 mg, 0.137 mmol) was dissolved in absolute acetonitrile (1.3
ml) under argon. The latter solution was added dropwise by syringe to the
Ph
solution of 5 at room temp. After stirring for 12-16 h, the solvent was removed under reduced pressure
and the solid yellow residue was exposed to oil pump vacuum for 2 h at rt. The crude yield is 92% (72
mg; 0.12 mmol), but due to the air- and moisture-sensitive nature of the product, this substance was
not characterized by any spectroscopic technique.
1-(Benzyloxycarbonyl)-piperidone (22) was prepared as described by Savoia et al.12 :
In a three-necked round-bottomed flask equipped with a mechanical stirrer, a
pressure-equalizing dropping funnel and an N2-inlet, -valerolactam (21; 37.94 g;
N
O
O
OB n
382.8 mmol) is dissolved in anhydrous THF (400 ml). The solution is cooled to –
78°C, n-BuLi (2.5M in THF; 161 ml; 402.5 mmol) is added dropwise with stirring.
After stirring the solution for 30 minutes a solution of CbzCl (55 ml; 386.9 mmol)
in THF (345 ml) is added dropwise, and the reaction mixture is stirred at –78°C for 4h, giving a
yellow solution. The reaction is quenched with aqueous NH4Cl (550 ml) and the organic phase is
extracted with diethylether (4x 250 ml), dried with MgSO4, filtered, and solvent is removed under
reduced pressure to give crude product in 87% as a yellow oil, which is purified by column
chromatography, eluting with EtOAc/PE (1/4) to give 52.7 g (223 mmol) of pure product in 58% as a
colouless oil. Rf = 0.3 in EtOAc/PE=1/2;– IR: 1770, 1720 cm-1; 1H-NMR:  1.72-1.84 (m, 4H), 2.52
(t, 2 H, J=6.9 Hz), 3.72 (t, 2H, J=6 Hz), 5.27 (s, 2H), 7.28-7.43 (m, 5H). This is correct according to
literature12. – 13C NMR (100MHz):  20.0, 22.3, 34.6, 46.3, 67.9, 127.7-127..8, 127.9, 128.0, 128.3,
135.4, 153.8, 170.8. There is no literature description known of the 13C NMR spectrum.
30
1-(Benzyloxycarbonyl)-2-methoxypiperidine (23b) was prepared using two different methods
Method I: by reducing 22 to the hemi-acetal 23a with LiEt3BH, followed by
making the acetal 23b using Scandium(III)triflate in CH2Cl2/MeOH, as described
N
O
OMe
OB n
by Kobayashi et al 14 .
To a solution of 1-benzyloxycarbonyl piperidone (7) (875 mg; 3.75 mmol) in dry
THF (4 ml) was added a 1.0 M solution of LiEt3BH in THF (4.1 ml; 4.1 mmol) at
-78 °C. The reaction mixture was stirred for 1 h at the same temperature, and the reaction was
quenched with water (1 mL) and warmed to rt. To the mixture were added a saturated aqueous
NaHCO3 solution (10 mL) and then 30% aqueous H2O2 solution (2 mL). After stirring for 1 h, the
mixture was extracted with EtOAc two times. The combined organic layers were washed with water
and brine, dried with MgSO4, filtered, and solvent was removed under reduced pressure. The crude
product was purified by column chromatography to afford 648 mg (2.75 mmol) of product 23a in 73%
yield as a colorless oil.
Then a solution of Sc(OTf)3 (9.7 mg; 27.5 mol) and 8 (648 mg; 2.75 mmmol) in a mixture of CH2Cl2
(3.6 ml) and MeOH (1.8 ml) was stirred for 3 h at rt. The reaction was quenched with a saturated
aqueous NaHCO3 solution, and the mixture was extracted with CH2Cl2 twice. The combined organic
layers were washed with brine, dried with MgSO4, filtered, and solvent was removed under reduced
pressure. The crude product was purified by silica gel chromatography to give 262 mg (1.1 mmol) of
product 23b in 38% as a colorless oil. Also 348 mg of starting material 24a was recovered (54%).
Overall yield 22 23b = 42% (lit. 84%) over two steps.
Method II: using NaBH4 in MeOH, followed by H2SO4 in MeOH, in one-pot fashion, according to a
procedure by Speckamp et al.13.
In a three-necked round-bottomed flask equipped with a magnetic stirrer and a connection to an N2line 7 (3.73 g; 15.9 mmol) is dissolved in MeOH (100 ml) and cooled to 0°C. NaBH4 (2.01 g; 54.2
mmol) is added, and stirred for 2 h at 0°C, after which is added H2SO4 in MeOH (2M) until pH=2, and
again stirred for 2 h at 0°C. The reaction is quenched with KOH in MeOH (1M) and filtered through
HyFlow to remove boron salts; evaporation gives crude product, which is purified by column
chromatography, eluting with EtOAc/PE = 1/2 to give 2.3 g (9.3 mmol) of product 23b in 54% as a
colourless oil.
Data for N,O-hemiacetal 23a: Rf=0.30 in EtOAc/PE=1/2; 1H NMR:  1.44-1.90 (m, 7H), 3.18 (br t,
1H), 3.89 (br d, 1H,), 5.15 (s, 2H), 5.79 (m, 1H), 7.32-7.40 (m, 5H);
Data for N,O-acetal 23b: Rf=0.55 in EtOAc/PE=1/2; – IR: 3050, 2941, 1703 cm-1; 1H-NMR, mixture
of rotamers:  1.25-2.03 (m, 6H), 3.00(m, 1H), 3.17 (s., 1.5H), 3.25 (s., 1.5H), 3.95 (m, 1H), 5.15 (m,
2 H), 5.34 (br.s., 0.5H), 5.43 (br.s., 0.5H), 7.25-7.48 (m, 5H) –
13
C NMR (100MHz, mixture of
rotamers):  18.3, 24.8-25.0, 29.9, 30.2, 38.6, 38.9, 54.3, 54.4, 66.9, 67.1-67.3, 81.9, 127.6, 127.8,
128.0, 128.9, 136.5, 155.6. This is correct according to literature14.
31
1-(Benzyloxycarbonyl)-2-allylpiperidine (24) was attempted using three methods
Method I: using chiral Lewis acid 4 as a catalyst, in a procedure by Braun et
al.5a, and different variations thereof. The original procedure is described below.
N
O
In a 50-ml Schlenk vessel equipped with a magnetic stirrer, a septum, and a
OBn
connection to a combined nitrogen/vacuum line, a solution of the titanium
complex 4 in absolute CH2Cl2 (3.54 mM, 20 ml, 0.0709 mmol) was stirred at -78°C under argon. In a
second 25-ml two-necked flask with the same setup, 23b (92.3 mg, 0.37 mmol) was dissolved in
absolute CH2Cl2 (5 ml) and subsequently added dropwise via cannula to the solution of the titanium
complex 4. Allyltrimethylsilane (70 l, 0.44 mmol) was then injected by syringe. The mixture was
allowed to warm to 0°C over 6 h, and stirring was continued for another 16 h at the same temperature.
After the addition of a saturated aqueous solution of NH4F (15 ml), the organic layer was separated,
and the aqueous phase was extracted with CH2Cl2 (3 x 15 ml). The combined organic layers were
washed with a saturated aqueous solution of NaF (10 ml) and dried with MgSO4. The solvent was
removed on a rotary evaporator, giving yellow oil as crude product, which was determined to be a
mixture of the eliminated product 23c in 24% yield, starting material 23b, ligand 19, and decompition.
The variations were the catalyst loading (10 or 20 mol%), the amount of nucleophile (1.2, 2 or 10 eq
of allyltrimethylsilane), the reaction time (from 18-60 h) and the warm-up time (from 6-22 h).
Also the active catalyst has been made in situ (see procedure 4) prior to addition of 23b, also using a
fresh batch of TiF4.
Method II: using BF3•OEt2, according to a procedure by Berkheij26.
In a three-necked round-bottomed flask equipped with a mechanical stirrer and an N2-inlet, 23b (502
mg; 2.02 mmol) and allyltrimethylsilane (0.63 ml; 4.0 mmol) are dissolved in anhydrous CH 3CN (10
ml), and cooled to 0°C. BF3•OEt2 (0.51 ml; 4 mmol) was added at 0°C and the reaction mixture was
stirred for 1h at 0°C and then 3 h at rt. Although the conversion was only 50% on TLC, workup was
commenced as following. The reaction mixture was poured onto an aqueous saturated NaHCO 3solution, filtered and extracted with EtOAc (3x200 ml), washed with brine (2x), dried with MgSO4,
filtered and the solvent was removed under reduced pressure, yielding the crude product. This is
purified by column chromatography, eluting with EtOAc/PE = 1/9 to give 98 mg (0.38 mmol) of pure
product 24 in 40% (based on 50% conversion) as a white powder.
Method III: Using racemic binol hydrogen phosphate rac-10a as catalyst.
In a two-necked round-bottomed flask equipped with a mechanical stirrer and an N2-inlet, 23b (58.6
mg; 0.235 mmol) and racemic binol hydrogen phosphate rac-10a (4 mg; 0.012 mmol) are dissolved in
anhydrous absolute CH2Cl2 (2 ml). Allyltrimethylsilane (75 l; 0.47 mmol) was added and the reaction
mixture was stirred overnight. Although the conversion was only about 40% according to TLC, the
reaction mixture was purified by column chromatography, eluting with EtOAc/PE (1/9) to give the
eliminated product 23c (26 mg; 0.13 mmol; 53%).
Data for allyl product 24: Rf=0.35 in EtOAc/PE=1/4; IR: 3066, 3032, 2938, 2861, 1693, 1642, 1498,
1450, 1423 cm-1; 1H-NMR:  1.34-1.45 (m, 1H), 1.47-1.60 (m, 5H), 2.22-2.29 (m, 1H), 2.39-2.46 (m,
32
1H), 2.81-2.89 (m, 1H), 4.04-4.07 (m, 1H), 4.38 (br.m., 1H), 4.98-5.07 (m, 2H), 5.11(d, 1H), 5.14 (d,
1H), 5.65-5.73 (m, 1H), 7.29-7.38 (m, 5H).
Data for eliminated product 23c: Rf=0.46 in EtOAc/PE=1/4; 1H-NMR:  1.57 (m, 2H), 1.83 (m,
2H), 2.06 (m, 2H), 4.87 (m, 0.5H), 4.99 (m, 0.5H), 5.19 (s, 2H), 6.81 (m, 0.5H), 6.90 (m, 0.5H), 7.297.38 (m, 5H).
6.2
Brønsted acid chemistry
S-(2-Nitrophenyl)sulfenylamine (29) :
At 0°C, 2-nitrophenylsulfenylchloride 30 (1.8g; 9.4 mmol) was added in portions to
H2N
S
a solution of aqueous NH3 (25% wt; 10 ml; 140 mmol) in THF (40 ml) and MeOH
(5 ml), and stirred for 2 h at rt. A saturated NH4Cl-solution was added, and after
O2N
separation the aqueous layer was extracted with Et2O.The collected organic layers were dried with
MgSO4 and solvent was removed under reduced pressure. Recrystallization from EtOAc gave 1.4 g
(8.3 mmol) of product in 88% over two fractions as yellow crystals.
H-NMR:  2.74 (br s, 2H), 7.26 (d, 1H), 7.70 (m, 1H), 8.15 (m, 1H), 8.29 (m, 1H).
1
Methyl 2-(2-nitrophenylsulfenyl-imino)acetate (31):
S-(2-nitrophenyl)sulfenylamine 29 (1.7 g; 10 mmol), racemic binol hydrogen
OMe
O
phosphate rac-10a (17.4 mg; 50 mol, 2mol%) and MgSO4 (3 g) were added
N
to a stirred solution of methyl glyoxate methyl hemi-acetal (1.26 g; 10.5
S
O 2N
mmol) in CH2Cl2 (50 ml). After stirring for 5 h, the catalyst was removed by
addition of 1 g of silica, stirring for 5 minutes and subsequent filtration over a bed of 5 g silica.
Washing with EtOAc/PE (1/1; 60 ml) gave crude product, of which crystallization from EtOAc/PE
gave 1.137 g of product (57%) as yellow crystals. As the reaction had not gone to completion, the
mother liquor was evaporated and reacted with 0.5 ml methyl glyoxate methanol adduct, rac-10a
(7 mg; 2 mol%) and 10 ml in CH2Cl2, and worked-up in the same manner to give another 0.57 g of
product. This reaction did go to completion, to give a total yield of 2.04 g (8.5 mmol) of product 31 in
85% yield (from 29).
mp= 120-121°C – 1H-NMR (DMSO, 80°C):  3.87 (s, 3H), 7.54-7.59 (m, 1H), 7.92 (t, 1H), 8.32-8.36
(m, 2H), 8.38-8.50 (br s, 1H) –
13
C NMR (100 MHz, DMSO): 50.6, 125.3, 125.8-126.2, 133.9,
134.4, 137.6, 142.5, 149.1, 161.5 . This is correct according to literature.27
Commercially available (Fluka) 2,2-dimethoxy-1,1’-binaphthyl (25) was dried under vacuum at 100°C
for 3 h to remove water and then recrystallized from refluxing acetone.
33
(R)-3,3’-Bis(dihydroxyborane)-2,2’-dimethoxy-1,1’-dinaphthyl (26a) was prepared using a slightly
modified version of the procedure described by Jørgensen et. al 16:
B(OH)2
In a 500 ml three-necked round-bottomed flask equipped with a N2-inlet were
placed dry Et2O (300 ml) and TMEDA (8.1 ml; 53.7 mmol). To this solution
OMe
OMe
B(OH)2
was added 1.6 M n-BuLi in hexane (36.5 ml, 58.4 mmol). The solution was
stirred for 1 h at rt, 2,2-dimethoxy-1,1’-binaphthyl 25 (5.97 g; 19.0 mmol) was
added in one portion, and the reaction mixture was stirred for 4 h. The
resulting yellow-orange suspension was cooled to -78 °C, and B(OEt)3 (21 ml,
123 mmol) was added via syringe over a period of 10 min. The solution was allowed to warm to room
temperature and was left stirring overnight. The reaction mixture was cooled to 0 °C, 1 M HCl (160
mL) was added, and the reaction mixture was stirred for 4 h. The phases were separated, and the
organic phase was washed twice with 1 M HCl (100 mL) and saturated aqueous NaCl (100 mL) and
dried with MgSO4. The solvent was removed under reduced pressure, and the resulting white solid was
recrystallized from toluene and a CH2Cl2/PE-mixture to give 2.6 g (6.4 mmol) of product as off-white
crystals in 34% yield.
[]D= -168.5° (c=1 in CHCl3; lit.16: [D=-153.4°, c=1 in CHCl3); mp= 225-230°C (lit.16 >250°C); IR:
1588, 1619, 2838, 2938, 3389 cm-1; 1H-NMR:  3.31 (s, 6H), 5.98 (br.s. 4 H), 7.16 (d, 2H, J=7.2 Hz),
7.32 (t, 2H, J= 6.5 Hz), 7.45 (t, 3H, J= 8Hz), 7.99 (d, 2H, J=8 Hz), 8.62 (s, 2H) – 13C NMR (100 MHz,
DMSO):  60.8, 123.0, 124.6, 125.3, 126.8, 129.1, 130.0, 134.6, 135.7, 159.9. This is correct
according to literature17. The measured melting point is lower than the literature melting point because
the sample was a glass instead of crystals.
(R)-3,3’-Bis(4-nitrophenyl)-4-yl-[1,1’]binaphthalenyl-2,2’-diol (27) was prepared using a slightly
modified procedure of Akiyama 9,15:
NO2
To a suspension of 26a (802 mg; 2.00 mmol), Ba(OH)2•8H2O (1.63
g; 6.24 mmol), and Pd(PPh3)4 (414 mg; 0.394 mmol) in degassed
dioxane/water (20 ml, 3:1/v:v) were added 4-bromonitrobenzene
OH
(1.05 g; 5.20 mmol). The reaction mixture was heated at reflux for 25
OH
h and cooled to rt overnight. Dioxane was evaporated, and the
resulting residue was redissolved in CH2Cl2, washed with 1M HCl
solution and brine, dried with anhydrous MgSO4, and concentrated
NO2
under reduced pressure to give crude products. To the solution of the
crude products in CH2Cl2 (75 ml) was added a solution of BBr3 (9.5 mmol) in CH2Cl2 (1 M; 9.5 ml) at
0 ˚C. After being stirred at rt for 16 h, the reaction mixture was quenched by dropwise addition of H 2O
(33 ml) at 0 ˚C for 10 min, extracted with CH2Cl2. The combined organic layers were washed with
brine, dried with MgSO4, and solvent was removed under reduced pressure. Purification by column
chromatography gave 909 mg (1.7 mmol) of product as a dark yellow solid in 86%.
34
Rf=0.42 in EtOAc/PE=1/4; []D= -20.2° (c=0.93 ;lit.17: [D= -10.6°, c=1.0 in CHCl3); mp= 158164°C (lit. 215-233) – 1H NMR 5.78 (s, 2H), 7.27 (d, 2H, J=8 Hz), 7.38-7.48 (m, 4H), 7.95 (d, 4H,
J=8.8 Hz), 8.00 (d, 2H, J=8.0 Hz), 8.12 (s, 2H), 8.33 (d, 4H, J= 8.8 Hz). This is correct according to
literature, except for the specific rotation. It must be noted that this measurement was not fully
reliable, as the light transmission was very low.
NO2
(R)-3,3'-Bis(4-nitrophenyl)-1,1'-binaphthyl
phosphate
(10c)
was
17
prepared using a slightly modified procedure of Akiyama :
To a solution of 27 (49 mg; 0.093 mmol) in pyridine (0.5 ml) was
O
O
added phosphorus oxychloride (25 L; 0.25 mmol) at rt under N2
P
O
OH
atmosphere. After stirring at rt for 4 h, the reaction mixture was
quenched by addition of H2O (20 L) at 0 ˚C and stirred for 2 h at rt.
NO2
After evaporation of pyridine under vacuum, 6M HCl (4 ml) was
added to the residue at 0 ˚C. The mixture was refluxed for 2 h. After cooling to 0 ˚C, the resulting
solids were collected by filtration, washed with H2O to give crude material (89%). This was dissolved
in CH2Cl2 and poured into hexane to give 10c as very finely divided crystals (18 mg; 0.03 mmol) in
33% yield. (lit. = 83%). The rest of the product can be obtained, but due to the small size of the
crystals, only by very tedious filtration. Therefore the Terada-procedure is recommended.
Terada-procedure10: The binol-derivative (0.5 mmol) was dissolved into 1 ml of pyridine under N2
atmosphere. To the resulting mixture was added phosphorous oxychloride (1.5-2.0 eq) at rt and the
reaction mixture was stirred for 3 hours. 1 ml of H2O was added and the resulting suspension was
stirred for additional 30 min. CH2Cl2 was added and all pyridine was removed by reverse extraction
with 1 M HCl. Organic phase was dried with MgSO4 and purified by column chromatography. Product
10 was isolated in quantitative yield.
This procedure was found only after the practical work was done. It must be noted that in Terada’s
work
the
3,3’-substituents
are
non-functionalized
aryl
groups.
The
presence
of
a
nitrophenyl-group at that position could influence the yield and ease of this procedure.
[]D= ° (c=30.6 ;lit.16: [D=-34.7°, c=0.51 in EtOH); mp= 222-235°C (lit.17: 223.5-249) – 1H NMR
(400 MHz, CDCl3) = 8.01 (d, 2H, J=8.2 Hz), 7.97 (s, 2H), 7.92 (d, 4H, J=8.1 Hz), 7.60-7.55 (m, 6H),
7.46-7.21 (m, 4H);
31
P NMR (376 MHz, CDCl3 ) = 1.63;
C NMR(100 MHz, CDCl3) = 148.83,
13
144.97, 144.52, 144.43, 143.70, 141.09, 132.58, 131.82, 131.39, 131.17, 130.70, 128.59, 127.39,
127.06, 126.37, 123.09, 122.98, 96.11. This is correct according to literature, except for the specific
rotation. It must be noted that this measurement was not fully reliable, as the light transmission was
very low.
35
Procedure for the Aza-Friedel-Crafts reaction of indole 32 and Methyl 2-(2-nitrophenylsulfenylimino)acetate 31, preparation of (S)-methyl 2-(1H-indol-3-yl)-2-(2-nitrophenylsulfenylamino)acetate
33: Indole 32 (0.11 mmol) and methyl 2-(2-nitrophenylsulfenyl-
OMe
O
H
imino)acetate 31 (0.1 mmol) were placed in a 10 ml round-bottomed
NH
flask and the solvent (1-2 ml) was added, followed by the catalyst 10
S
N
H
(2 mol). The reaction was monitored on TLC and HPLC, and after
O2N
completion the product is purified by column chromatography, eluting
with EtOAc/PE (1/2) to give product in 92-99% yield. In reactions that were carried out below rt,
solvents were cooled prior to addition of catalyst.
[]D= 106° (c=0.54 in CHCl3) of enantiomerically pure compound18; mp= 172.5-174°C – 1H-NMR: 
3.74 (d, 1H, J = 7.6 Hz), 3.79 (s, 3H), 4.92 (d, 1H, J=8 Hz), 7.20-7.31 (m, 3H), 7.23 (d, 1H, J= 7.6
Hz), 7.54 (t, 1H, J=7.5 Hz), 7.75 (d, 1H, J=8 Hz), 8.12 (d, 1H, 8.4), 8.23 (br.s., 1H), 8.27 (d, 2H, J =
8.4Hz).
C-NMR (100MHz):  52.6, 60.5, 111.5, 112.6, 119.0, 120.5, 122.9, 123.3, 124.7,
13
124.9,125.61, 125.64, 133.6, 136.4, 142.7, 144.8, 173.1. IR (neat): 3405, 3080, 2950, 1733 – HRMS
(FAB): e/z calculated for C17H15N3O4S, (M+H) 358.0862, Found 358.0863 - Elemental analysis:
calculated for C17H15N3O4S: C, 57.13; H 4.23; N, 11.76; found: C, 57.18; H, 4.27; N, 11.75 The
absolute configuration was determined by X-ray crystallography as the S-enantiomer.18
Procedure for the Pictet-Spengler condensation of Nps-protected tryptamine 35 and hexanal 36,
preparation of 2-(2-nitrophenylsulfenyl)-1-pentyl-1,2,3,4-tetrahydroindolo[2,3-C]pyridine d) (37):
n-Hexanal 36 (18.1 l; 0.15 mmol) and Nps-protected tryptamine 35
(31.3 mg; 0.10 mmol) were dissolved in 1 ml of CHCl3 in a 10 ml
N
S
NO2
round-bottomed, followed by the catalyst (1.2 mg; 2 mol). The
*
reaction was monitored on TLC and HPLC, and after completion the
N
H
product is purified by column chromatography, eluting with
EtOAc/PE (1/5) to give the product in quantitative yield.
H-NMR:  0.86 (br.s., 3H), 1.30 (br.s. 5H), 1.52-1.63, 2.04-2.19 (m, 2H), 2.82-3.58 (7 broad signals,
1
5H, mixture of rotamers), 4.23 (s, 1H), 7.15-7.37 (m, 6H), 7.54-7.7.56 (m, 1H), 7.69-7.95 (m, 2H),
8.31-8.33 (m, 1H).
13
C-NMR (DMSO-d6):  14.0, 20.1, 22.6, 26.4, 31.8, 35.9, 48.5, 63.8, 108.6,
110.8, 118.2, 119.6, 121.9, 124.6, 124.8, 126.0, 127.2, 133.9, 135.9.
36
Chapter 7 References
1
Reviews on enantioselective reactions: Mannich: Notz, W.; Tanaka, F.; Watanabe, S.-I.; Chowdari,
N.S.; Turner, J.M.; Thayumanavan, R.; Barbas III, C.F.; J. Org. Chem. 2003, 68, 9624-9634; DielsAlder: Corey, E.J.; Angew. Chem. Int. Ed. 2002, 1650-1667; Jørgensen, K.A.; Eur. J. Org. Chem.
2004, 2093-2102 (hetero Diels Alder); Henry: Luzzio, F.; Tetrahedron 2001, 915-945; Michael:
Christoffers, J.; Baro, A.; Angew. Chem. Int. Ed. 2003, 1688-1690; Friedel-Crafts: Bandini, M.;
Melloni, A.; Umani-Ronchi, A.; Angew. Chem. Int. Ed. 2004, 550-556; Strecker: Gröger, H.; Chem.
Rev. 2003, 2795-2827.
2
Clayden, J. P.; Greeves, N.; Warren, S.; Wothers, P. D.; Organic Chemistry, 1st Ed.., 2001, Oxford
University Press, Oxford; Carey, F.C.; Sundberg, R.J.; Advanced Organic Chemistry, part B, 4th Ed.;
2001; Kluwers Academic Publishers/Plenum Publishers, New York.
3
a) Speckamp, W.N.; Molenaar, M.J.; Tetrahedron 2000, 3817-3856, b) Maryanoff, B.E.; Zhang, H.-
C.; Cohen, J.H.; Turchi, I.J.; Maryanoff, C.E.; Chem. Rev., 2004, 1431-1628.
4
a) General review: Yamamoto, H.; Lewis Acids in Organic Synthesis, Vol. 1 and 2, Wiley-VCH,
Weinheim, 2000. - b) TiIV: Narasaka, K.; Iwasawa, N.; Inoue, M.; Yamada, T.; Nakashima, M.;
Sugimori, J.; J. Am. Chem. Soc. 1989, 111, 5340-5345. - FeIII: Corey, E. J. ; Imai, N. ; Zhang, H. Y.; J.
Am. Chem. Soc. 1991, 728-729. c) TiIV: Mikami, K.; Terada, M.; Nakai, T.; J. Am. Chem. Soc. 1989 1940-1941. - CuII: Evans, D. A. ;
Miller, S. J.; Lectka,T.; J. Am. Chem. Soc. 1993, 6460-6461. - ZnII: Evans, D. A. ; Kozlowski, M. C. ;
Tedrow, J. S. Tetrahedron Lett. 1996, 7481-7484. AlIII: Corey, E. J. ; Sarshar, S. ; Bordner, J. ; J. Am.
Chem. Soc. 1992, 7938-7939; YbIII: Kobayashi, S.; Hachiya, I.; Ishitani, H.; Araki, M. Tetrahedron
Lett. 1993, 4535-4538.
5
a) Fleischer, R.; Wunderlich, H.; Braun, M.; Eur. J. Org. Chem. 1998, 1063-1070. b) Braun, M.;
Kotter, W.; Angew. Chem. Int. Ed. 2004, 514-517, c) Devant, R.; Mahler, U.; Braun, M.; Chem. Ber.
1988, 397-406
6
a) Fan, Q.; Lin, L.; Liu, J.; Huang, Y.; Feng, X.; Zhang, G.; Org. Lett. 2004, 2185-2188; b) Li,
Y.;He, B.; Qin, B.; Feng, X.; Zhang, G.; J. Org. Chem. 2004, 69, 7910-7913
7
RuII : Noyori, R.; Ohkuma, T.; Angew. Chem. Int. Ed., 2001, 40-73; Coulon, E.; de Andrade,
M.C.C.; Ratovelomanana-Vidal, V.; Genêt, J.-P.; Tet. Lett., 1998, 6467-6470 (Ru only used for
hydrogenations) - PdII: Trost, B.M.; Toste, F.D.; J. Am. Chem. Soc., 1999, 3543. Nakamura, K.;
Nakamura, H.; Yamamoto, Y.;J. Org. Chem, 1999
8
Dalko, P.I.; Moisan, L.; Angew. Chem. Int. Ed. 2001, 3726-3748; Taylor, M.S.; Jacobsen, E.N.; J.
Org. Chem. Soc. 2004, 10558-10559; R. Schreiner; Chem. Soc Rev. 2003, 289-296.
9
Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K.; Angew. Chem. Int. Ed., 2004, 1566-1568
10
a) Uraguchi, D.; Terada, M; J. Am. Chem Soc. 2004, 5356-5357; b) Uraguchi, D.; Sorimachi K.;
Terada, M; J. Am. Chem Soc. 2004, 11804 – 11805
11
Texier-Boullet, F.; Synthesis, 1985, 679-80
12
Giovannini, A.; Savoia, D.; Umani-Ronchi, A.; J. Org. Chem. 1989, 228-234
37
13
Hubert, J.C.; Wijnberg, J.B.P.A.; Speckamp, W.N.; Tetrahedron 1975, 1437-1441
14
Okitsu, O.; Suzuki, R.; Kobayashi, S.; J. Org. Chem. 2001, 809-823
15
Wipf, P.; Jung, J.-K.; J. Org. Chem. 2000, 6319-6337
16
Simonsen, K.B.; Gothelf, K.V.; Jørgensen, K.A.; J. Org. Chem. 1998, 7536-7538
17
Akiyama T., unpublished results
18
Wanner, M., unpublished results
19
Greene, T.W.; Wuts, P.G.M.; Protective Groups in Organic Chemistry, 3rd ed., 1999, John Wiley &
Sons Inc., New York, p. 600-601
20
http://home.planet.nl/~skok/techniques/hplc/eluotropic_series_extended.html#3
21
Johannsen, M.; Chem. Commun. 1999, 2233-2234; Wenzel, A.G.; Jacobsen, E.N.; J. Am. Chem.
Soc. 2002, 12964-12965; Fraser, P.K.; Woodward, S.; Chem. Eur. J. 2003, 776-783;
22
Zhang, H.; Chan, K.S.; J. Chem. Soc., Perkin Trans. 1, 1999, 381–382
23
Blay, G.; Fernandez, I.; Marco-Alelaxandre, A.; Pedro, J.R.; Tet. Assym. 2005, 1207-1213; Pu L.;
Yu H.B.; Chem. Rev. 2001, 757-824;
24
Magnier, E.; Lunglois, Y.; Tetrahedron 1998; 6201-6258; Pouilhès, A.; Duval-Lungulescu, M.;
Lambel, S.; Léonce, S.; Langlois, Y.; Tet. Lett 2001, 8297-8299
25
McNulty, J.; Still, I.W.J.; Curr. Org. Chem., 2000, 121-138; Rinehart, K.L.; Kobayashi, J.; Harbour,
G.C.; Gilmore, J.; Mascal, M.; Holt, T.G.; Shield, L.S.; Lafargue, F.; J. Am. Chem. Soc., 1987, 3378.
26
Berkheij, M., unpublished results
27
Heyer, J.; Dapperheld, S.; Steckhan, E.; Chem. Ber. 1988, 1617-1623
38
Chirale zure katalysatoren voor asymmetrische addities
Hoofdvakstage Peter Hauwert, mei 2004 - juni 2005
Organische Synthese, prof. H. Hiemstra
Bij het doelgericht synthetiseren van kleine organische moleculen is het uiterst belangrijk om de
stereochemie te beheersen. Er zijn meerdere manieren om dit te doen, maar voor additiereacties is het
gebruik van chirale katalysatoren de handigste.
Additiereacties zijn reacties waarbij twee moleculen verbonden worden, meestal door een C-C-binding.
Dit gebeurt bijna altijd op zo een manier dat een mengsel van de twee spiegelbeelden van het product
wordt gevormd. Door het toevoegen van een asymmetrische katalysator is het mogelijk een voorkeur voor
een van de stereoproducten te creëren.
In dit onderzoek is de invloed van zure katalysatoren op enantioselectieve additiereacties bekeken, met als
doel het ontwikkelen van nieuwe synthetische methodes voor deze reacties.
Hiervoor zijn een Lewis zuur met een chiraal ligand (1) en een asymmetrisch Brønsted zuur (2)
gesynthetiseerd, en is bekeken of die de gewenste katalytische werking hebben. Beide waren al bekend
uit de literatuur1,2, maar waren nog niet toegepast op de beoogde reacties.
NO2
N
O
O
Ti
O
O
P
OH
O
F
F
NO2
2
1
Figuur 1: de onderzochte katalysatoren 1 en 2
Voor katalysator 1 is de reactie uit de literauur1 onderzocht onderzocht, wat helaas niet tot de verwachte
resultaten leidde. Dit is waarschijnlijk omdat deze katalysator zeer zuurstof- en vochtgevoelig is, en dus
alleen in een ‘glovebox’ uitgevoerd kan worden. Aangezien dit niet een algemeen toegankelijke techniek
is, is het onderzoek hierin gestaakt.
Si(CH3)3
katalysator 1 (10 mol%)
N
OCH3
Boc
N
N
Boc
Boc
Boc = C(O)OCH2C6H5 = aromatische beschermgroep voor N
Schema 1: De resultaten van katalysator 1
Katalysator 2 is getest op een nieuwe reactie, tussen indol en een beschermd imine. Dit was succesvoller,
aangezien de katalysator niet alleen het product in enantiomere overmaat opleverde in een bijna volledige
opbrengst, maar ook nog teruggewonnen en hergebruikt kon worden. Het onderzoek hieraan wordt
voorgezet, waarbij er variaties zullen worden gemaakt in de nitrophenyl-groepen aan de rechterkant van
de katalysator.
Verder is in dit onderzoek een nieuwe toepassing gevonden voor de Nps-beschermgroep (schema 2),
namelijk als hulp bij het stabiliseren van N-acyliminiumionen.
OCH3
OCH3
katalysator 2 (2 mol%)
O
H
O
+
N
H
NH
CHCl3, 50°C
N
Nps
99% opbrengst
50% e.e.
O2N
S
Nps
Nps = 2-nitrophenylsulfenyl
N
H
Schema 2: De resultaten van katalysator 2
1) Braun, M.; Kotter, W.; Angew. Chem. Int. Ed. 2004, 514-517, 2) Akiyama, T. et al.; Angew. Chem. Int. Ed., 2004, 1566-1568
39