Towards Auxiliary Mediated Peptide Cyclization
Employing an Allylic Amination/Acyl-Transfer
Cascade Reaction
Δ
Master Thesis
Sjoerd Slagman
HIMS, Synthetic Organic Chemistry (SOC), FNWI, UvA
First supervisor
Dr. Jan van Maarseveen
Second supervisor
Prof. Kees Elsevier
Professor
Prof. Henk Hiemstra
Abstract
Small cyclic peptides are of high biological and chemical interest. Cyclic peptides exhibit higher
bioavailability due to lower biodegradability, improved pharmacodynamic, and –kinetic properties,
due to a lesser degree of flexibility when compared to their linear counterparts. To cyclize small
peptides under laboratory conditions still remains a challenge. The amide bond in peptides mainly
occurs in the transoid form, which enhances linearity, which, for its part, prevents both termini from
coming in close proximity.
One way to overcome this is by first reacting both termini with an auxiliary by which these termini
get in close proximity of one another and then peptide would cyclize spontaneously. We envisioned
an auxiliary, which was based on first binding the C-terminus through standard peptide coupling and
subsequent allylic amination with the N-terminus of the linear peptide. Hereafter, the peptide would
then cyclize spontaneously through O-to-N acyl-transfer (figure 1, route A).
After successful development of an appropriate allylic amination procedure with the test substrate
(methyl cinnamyl carbonate) and nucleophile (H-Phe-Ot-Bu) we started synthesizing the envisioned
auxiliary. This auxiliary is o-OH methyl cinnamyl carbonate, through the hydroxyl group we would be
able to couple the C-terminus of the peptide and the N-terminus could then attack on the allylic
moiety. However, this auxiliary did not prove to be very stable at room temperature and very
sensitive to traces of acid. Therefore, the product after the final step (deprotection of the hydroxyl
moiety) was never isolated and follow-up chemistry (esterification) was initiated in a “one-pot”
fashion. This never reached the phase of peptide coupling, only development of the test substrate,
o-OAc methyl cinnamyl carbonate, was carried out.
This test substrate was then used in the allylic amination/O-to-N acyl-transfer sequence (figure 1,
route B). This did not result in full conversion of the substrate. Therefore, the catalyst loading was
tripled, full conversion was now achieved. However, the desired product could not be observed.
Instead, several byproducts were formed in which the acetyl group was cleaved before the allylic
amination could take place. Therefore, we concluded that this methodology is not suitable for small
peptide cyclization, since the allylic amination reaction is far slower than the acyl-transfer.
2
Graphical abstract
Figure 1 graphical abstract displaying the envisioned route towards cylic peptides (in blue, A) and the failed allylic
amination/acyl-transfer cascade reaction (in red, B)
3
List of Abbreviations
AA
AAA
Ac
Ala
Alk
Arg
Asp
Bn
Boc
Bt
Bu
c
Cat.
cod
Conv.
D
d
dbcot
DCC
DCM
DEPBT
DIBAL-H
DIPEA
DMAP
DMSO
dppe
E
ee
Et
et al.
G
Gly
HATU
His
HPLC
i
L
LCMS
Leu
LG
M
m
Me
Mol%
n
Amino acid
Asymmetric allylic amination
Acetyl
Alanine
Alkyl
Arginine
Aspartic acid
Benzyl
Tert-butyl carbonate
1H-Benzo[d][1,2,3]triazol-1-yl
Butyl
Cyclo
Catalyst
1,5-Cyclooctadiene
Conversion
Aspartic acid
Doublet
Dibenzo[a,e]cyclooctatetraene
N,N’-Dicyclohexylcarbodiimide
Dichloromethane
3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one
Diisobutylaluminium hydride
N,N-Diisopropylethylamine
4-Dimethylaminopyridine
Dimethyl sulfoxide
1,2-Bis(diphenylphosphino)ethane
Entgegen
Enantiomeric excess
Ethyl
Et alii
Glycine
Glycine
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
Histidine
High pressure liquid chromatography
Iso
Ligand
Liquid chromatography-mass spectrometry
Leucine
Leaving group
Metal
Multiplet
Methyl
Molar percentage
Number
4
n
NBS
NMR
Nuc
o
p
Pfp
PG
Ph
Phe
PPTS
Pr
Pro
q
R
R
s
Ser
t
t
TBAF
TBS
THF
THP
TIPS
TLC
Trp
Z
Normal
N-Bromosuccinimide
Nuclear magnetic resonance
Nucleophile
Ortho
Para
Pentafluorophenyl
Protecting group
Phenyl
Phenylalanine
Pyridinium para-toluenesulfonate
Propyl
Proline
Quartet
Arginine
Rest group
Singlet
Serine
Tert
Triplet
Tetra-n-butylammonium fluoride
Tert-butyldimethyl silyl
Tetrahydrofuran
Tetrahydropyr-2-yl
Triisopropylsilyl
Thin layer chromatography
Tryptophan
Zusammen
5
Table of Contents
Abstract
2
Graphical abstract
3
List of Abbreviations
4
Table of Contents
6
Chapter 1, Introduction
7
Cyclic peptides
Peptide cyclization
7
10
Difficulties in cyclization
10
How to overcome these issues
12
Project objectives
Chapter 2
Development of a suitable Allylic Amination Methodology
16
20
Allylic amination
20
Results
21
Chapter 3
Synthesis of the Auxiliary
Results
Chapter 4
28
Coupling of the Auxiliary to an Amino Acid
Results
Chapter 5
28
33
33
Testing the Allylic Amination/Acyl-transfer Sequence
Results
35
35
Conclusion and Outlook
37
Acknowledgments
39
Experimental section
40
List of References
51
6
Chapter 1, Introduction
Cyclic peptides
Peptides are important building blocks of nature. Peptides are build up from molecules called αamino acids. In total there are 21 proteogenic amino acids. These amino acids are at the basis of all
life on earth. A amino acid consists of a primary amine and a carboxylic acid moiety, which flank a
carbon atom bearing a side chain. This side chain provides the diversity within amino acids. The side
chain can be apolar, as in valine, or more polar as, for example, serine. There is also a big variety in
the acidity of these side chains; from very acidic, glutamic or aspartic acid, to basic, lysine for
example (figure 2).
Figure 2 variety in amino acids
By combining these amino acids through amide-bond formation, one can create peptides. The
amount of peptides that can be made from these 21 proteogenic amino acids is virtually endless.
Furthermore, they can differ immensely in length; from small oligopeptides to immense proteins.
The diversity in structure is also the basis for the biological activity and specificity of peptides. There
are many different ‘jobs’ a peptide or protein can have. They can, for example, be either an enzyme,
act as a medicine or work as cell signalling protein.
Although many examples of peptide structures have been summed up above, there is yet another
very important class of peptides, these are the cyclic peptides. The class of cyclic peptides consists of
a chain of amino acids where one part of the chain is connected to another part of the chain in such
a way that a cyclic structure arises. These cyclic peptides are both biologically and chemically
interesting targets. In 2011 Yudin and White published an elaborate review on this topic.1 There are
several ways to connect both ends of the peptide. This can be either a side chain-to-side chain, headto-side chain, side chain-to-tail or head-to-tail connection. Within this report only head-to-tail
connections within small peptides (consisting of two to seven amino acids) will be discussed (figure
3).
7
R
CO2H
NH2
R’
Figure 3 sites for ring closure
This class of peptides has unique properties when compared to linear peptides. Where linear
peptides have charged termini, (most) cyclic peptides lack these, which makes them less
biodegradable and thereby their membrane permeability and bioavailability are enhanced. 2,3
Furthermore, cyclic peptides are less flexible than their linear counterpart, which, in general,
improves the pharmacodynamic and –kinetic properties.4
The first example of the use of such a relatively small cyclic peptide is Gramicidin S (figure 4).
Gramicidin S was first isolated in 1942 by Gause and Brazhnikova and was used as an antibiotic to
treat infections from superficial (gunshot) wounds, later on in the Second World War.5
Figure 4 Gramicidin S
8
Protein mimicry is an important tool in biochemistry. By creating a molecule, which consists of only
the active part of a certain protein, one might be able to mimic the effect of this protein. Integrins,
for example, play an important role in cell-matrix interactions, cell signaling etc. Integrin αVβ3 causes
tumor growth, inhibition of this function would diminish its ability to enhance tumor growth (figure
5). In the body integrin αVβ3 can be bound to an Arg-Gly-Asp (RGD) containing protein to prevent
further action of the integrin. To mimic this effect Gurrath, et al. developed a pentapeptide
containing this RGD moiety, which is a potent αVβ3 integrin antagonist.6
Figure 5 Integrin αVβ3
WF3161 is another example of a very successful cyclic peptide (figure 6). This tetrapeptide is a
promising cancerostatic in vitro.7
Figure 6 WF3161
Cyclic peptides are not only useful in biochemistry, but some can also act as organocatalysts. In 1993
Oku and Inoue used the diketopiperazine c-[His-Phe] to catalyze the addition of cyanide to
benzaldehyde in extremely high conversion and ee (figure 7).8
9
Figure 7 addition of cyanide catalyzed by c-[His-Phe]
Peptide cyclization
Due to their high bioactivity, small cyclic peptides are interesting target molecules for chemists. The
cyclization of small peptides, however, still remains a synthetic challenge. Below, the major issues
accompanied with the cyclization of small peptides are addressed and several possible solutions are
mentioned.
Difficulties in cyclization
Linearity
The main issue is the intrinsic linearity of a chain of amino acids. The amide bond exhibits double
bond character, which makes cyclization rather difficult. With common synthetic coupling
techniques oligomers and polymers are often the main side reactions.
In detail, the amide bond is stabilized by delocalization over the system, which gives the C-N bond
also partial double bond character. Hindered rotation over this C-N bond results in a cisoid/transoid
character (figure 8). However, the transoid conformer is energetically more favored than the cisoid
conformer. To lower the barrier towards cyclization at least one of the amide bonds should exhibit a
cisoid character. In this way both ends of the linear chain are in close proximity to each other, which
favors ring closure. For the synthesis of peptides with larger ring sizes however, this poses no
problem since they can more easily accommodate cisoid peptide bonds.9
Figure 8 equilibrium between the transoid and cisoid form of an amide
There are several techniques available to induce more cisoid character in the C-N bond, these will be
discussed later on in this chapter.
10
Site of ring closure
Another major issue is the sequence dependency of the cyclization reaction. Still there is no common
methodology to cyclize peptides in such a way that any amino acid can be at any position of the
linear chain.
This problem is addressed by Schmidt et al. In this well-known example the researchers wanted to
synthesize c-[Ala-Phe-Leu-Pro-Ala]. The previously mentioned problem of intrinsic strain was
overcome by making one end of the peptide so reactive that cyclization was more likely to occur. By
also doing the reaction at high dilution they were, in some cases, able to favor the intramolecular
reaction over the intermolecular reaction and thereby oligomerization and polymerization could be
prevented. The use of the pentafluorophenyl ester (Pfp ester) is a good way to make the C-terminus
of the peptide more reactive.
With this system all five possible lactamization reactions of the pentapeptide were investigated
(figure 9). However, merely the amide bond formation opposite to the proline moiety occurred
under formation of the monomer only. All other cyclizations gave either no yield, dimers or a
combination of monomer and dimer. This is a good example of the necessity of a cisoid inducing
moiety, such as proline. Due to the rigidity of proline the amide bond exhibits for 50% a cisoid
character and for 50% a transoid character.
Figure 9 effectiveness of ring closure with the Pfp ester at several sites
Clearly, steric hindrance on the nitrogen atom and high dilution are essential. With this example
Schmidt et al. nicely showed the complexity of peptide macrocyclization by addressing a lot of
common problems accompanied with the ring closure.10
Epimerization at the C-terminus
Another issue which arises when peptides are cyclized (or elongated for that matter) is
epimerization of the C-terminal residue. In general this happens through oxazolone formation. The
mechanism of epimerization is addressed later on in thesis.
11
How to overcome these issues
There are several ways to overcome these issues. White and Yudin nicely reviewed a wide range of
strategies which have been developed over the last decades. These methodologies can be roughly
divided over five classes. These will be treated separately, the following distinction is made.

Conformational elements which bring the two termini together

Metal ion-assisted cyclizations

Thio-mediated cyclizations

Cyclic peptides with non-amide linkers

Ring contraction after lactone formation
Conformational elements which bring the two termini together
Internal conformational elements include, for example, the use of proline as seen before. Also
methylation of the nitrogen atom brings the cisoid conformer of the C-N bond closer in energy to the
transoid conformer, which increases the chance of successful cyclization.11 Using a combination of Land D-amino acids will also enhance cyclization since the side chains will be further away from each
other in the cisoid conformer with respect to the all L-peptide (figure 10).12
Figure 10 the difference between a LL dipeptide and a LD dipetide
External conformational elements which enhance macrocyclization are based on the process of
isolation of the linear peptide from the bulk to mimic a diluted atmosphere. Such a methodology has
been developed within our group. This methodology relies on the use of a carbodiimide in which the
two nitrogen atoms bear a big carbosilane dendrimer, which insulates the intermediate and thereby
prevents oligomerization and polymerization (figure 11).13
12
Figure 11 peptide cyclization in which a carbosilane dendrimer ensures a pseudo-dilution atmosphere
Metal ion-assisted cyclizations
By using the affinity of metal ions for heteroatoms it is possible to pre-coordinate the peptide in a
cyclic form. Ye and co-workers used sodium ions to coordinate to the oxygen atoms of the backbone
amide carbonyl groups and thereby they were able to direct the two peptide termini towards each
other (figure 12).14
Figure 12 sodium ion assisted cyclization
13
Sulfur-mediated cyclizations
As mentioned before; biomimetic chemistry is a very important tool in synthesis. By making use of
easily formed cysteine derived thioesters one can bring both ends of a peptide in close proximity to
each other. The thioester can be formed from a reaction between a terminal cysteine or N-terminal
oxyethanethiol (figure 13) with the C-terminus of the peptide for example. This can then be followed
by S-to-N acyl-transfer to release the cyclic peptide.15
Figure 13 schematic representation of a 'native chemical ligation' acyl-transfer reaction sequence
Cyclic peptides with non-amide linkers
Not all cyclic peptide have a backbone merely consisting of amino acids. The family of
cyclotheonamides has an alkene linkage between both ends of the peptide (figure 14). For the ease
of synthesis a well-known fast intramolecular reaction can be used to couple both termini. In order
to synthesize such a cyclotheonamide one could use ring closing metathesis. Other linkers also exist,
such as, for example, 1,2,3-triazoles. Click chemistry is used to synthesize these linkers.
Figure 14 cyclotheonamide A
14
Ring-contraction after lactone formation
The fifth methodology involves a reaction sequence consisting of oxo-ester formation and acyltransfer, similar to the thioester-mediated cyclizations. Either by coupling both ends of the peptide
to an auxiliary, or by using a terminal serine (or threonine), one can create a intermediate, which is
suitable for cyclization. This short-living intermediate is then transformed to the cyclic peptide
through O-to-N acyl-transfer.
Auxiliary-mediated peptide cyclization has a long history in this group. Several methodologies have
been developed and employed in the cyclization of di-, tetra-, and pentapeptides. Even
homodiketopiperazines (dipeptides bearing a β-amino acid), which are difficult to obtain using
traditional lactamization techniques, have been synthesized in this way.
Two strategies towards cyclic peptides through a lactone intermediate will be discussed below. Both
have been developed within this group. In 2008 a salicylaldehyde-derived auxiliary was reported
(figure 15). First, one amino acid is coupled to this auxiliary through reductive amination after which
the amine is protected with a Boc-group. A second amino acid is then attached through
esterification. The non-auxiliary bound termini of both amino acids are now deprotected and could
be coupled with common peptide coupling techniques without racemization. Hereafter, the Bocgroup is removed from the amine after which fast spontaneous O-to-N acyl-transfer takes place.
After acidolytic removal of the auxiliary, inter alia, the main target c-[β-Ala-Phe] could be obtained.16
Figure 15 salicylaldehyde derived auxiliary mediated peptide cyclization
15
Recently another strategy employing an aza-michael addition and the earlier mentioned O-to-N acyltransfer has been reported (figure 16). Here, commercialy available, o-hydroxy-β-nitrostyrene is
used as the auxiliary. In this methodology a dipeptide is connected to the hydroxyl moiety of the
auxiliary by esterification. After deprotection of the amine function and addition of base an azamichael addition of the amine to the double bond took place. This short-living intermediate
immediately undergoes ring contractive O-to-N acyl-transfer. Then, even under these mild
conditions, the auxiliary splits of spontaneously to release the sterically crowded homobislactam c[β-Ala-Trp].17
Figure 16 o-hydroxy-β-nitrostyrene mediated peptide cyclization
Project objectives
The goal of this project is to develop a new general synthetic methodology to create small cyclic
peptides through a tandem process of (asymmetric) allylic amination and O-to-N acyl-transfer. An
allylic amination procedure has to be developed, which allows polar amino acids to be used as
nucleophile. This procedure should then gradually be developed towards a system in which a O-to-N
acyl-transfer can take place within the auxiliary-peptide intermediate (figure 17).
16
Figure 17 overview of the proposed route towards cyclic peptides
First, the appropriate transition metal for the allylic amination reaction has to be chosen. Expensive
metals such as palladium and iridium are commonly used. With the correct ligand environment the
selectivity and activity of the metal can be tuned. A relatively stable and insensitive system is
required since we use very polar amines as nucleophile. As substrate we envision, to start with,
cinnamyl derivatives. These react relatively fast when compared to more sterically encumbered allylcontaining molecules and the outcome of the attack of the nucleophile on the stabilized π-allyl
fragment is easily adjusted (figure 18).
Figure 18 initial tests on cinnamyl derived substrates for a suitable allylic amination reaction
17
When the correct reaction conditions are found, an acetate group will be placed at the orthoposition of the cinnamyl derivative. Which will, preferably, be made out of o-OH cinnamyl
acetate/carbonate. In this way the hydroxyl group can, later on, also be coupled to amino acids or
peptides. In this manner we can test if, after allylic amination, the O-to-N acyl-transfer will take place
(figure 19).
Figure 19 first test system for the allylic amination/O-to-N acyl-transfer cascade
If this works, the auxiliary will be esterified to test if the O-to-N acyl-transfer will also take place
between two amino acids (figure 20).
Figure 20 tests for the allylic amination/O-to-N acyl-transfer sequence based on linear peptideproducts
Eventually, peptide cyclization should be tested by coupling a (di)peptide to the auxiliary. This is then
followed by deprotection of the amine, after which an allylic amination reaction can take place. Now
both ends of the peptide are in close proximity and cyclization should happen spontaneously. After
acidic cleavage of the auxiliary the cyclic peptide would be released (figure 21).
18
Figure 21 proposed allylic amination, O-to-N acyl-transfer sequence for the synthesis of cyclic peptides
We are well aware that this methodology will not prevent epimerization. However, the main goal is
to develop a quick and general methodology towards small, but epimerized, cyclic peptides.
19
Chapter 2 Development of a suitable Allylic Amination Methodology
The first goal of this project is the development of the allylic amination procedure in which an amino
acid nucleophile is reacted with a cinnamyl derived test substrate. Below the concept of allylic
amination is discussed and results of our search towards an appropriate procedure are displayed
(figure 22).
Figure 22 initial tests on cinnamyl derived substrates for a suitable allylic amination reaction
Allylic amination
In a Tsuji-Trost-type allylic substitution a carbon- or heteroatom-centered nucleophile attacks on a
transition metal-π-allyl complex. Allyl ethers, amines, and other substituted allyl fragments can be
synthesized in this way.
Allylic amination is especially interesting, since allylamines are useful versatile building blocks in
organic chemistry. When used as building block the double bond is often functionalized further
through epoxidation or dihydroxilation for example.
In the Tsuji-Trost-type allylic amination the transition metal-complex coordinates to the allylic
substrate under formation of the transition metal-π-allyl complex and liberation of a leaving group
(halide, acetate, carbonate or hydroxyl, figure 23). Now the nucleophile attacks and after release of
the product from the complex, the catalyst can enter another cycle. Dependent on the catalyst
environment several products can be formed. By choosing the correct (chiral) ligand one can finetune both regio- as well as enantioselectivity.18
20
Figure 23 general mechanism for the allylic amination reaction
The scope of the allylic amination reaction is very broad. A wide range of nucleophiles, from
sulfonamides to polar amines, can be used. Often the nucleophile needs to be deprotonated first to
be reactive enough for attack on the allyl fragment. Also many substrates are available for this
reaction, but common are the cinnamyl derived substrates.
Results
The first goal of this project is to develop a methodology, which allows amino acids to be used as
nucleophile in the allylic amination reaction. In 2003 Humphries and co-workers reported the use of
methyl, ethyl, and tert-butyl esters of amino acids as nucleophile in the allylic amination of (E)-1,3diphenylallyl acetate (figure 24). In order for us to be able to use this methodology, the system had
to be adjusted so that cinnamyl acetate can be used as substrate instead of a chalcone derivative.
Unfortunately when using the tert-butyl ester of valine a complex mixture of products was
obtained.19
Figure 24 unsuccessful first attempt for a suitable allylic amination reaction using palladium
21
A similar strategy, now starting from alkyl functionalized allylic acetates, was proposed by Trost et al.
(figure 25). Important was the use of a typical “Trost-type” ligand and the in situ liberation of the
amino acid from its HCl salt, which is different from the previously mentioned methodology. When
we employed this methodology, however, again a complex mixture was obtained and no clear
product formation could be observed. 20
Figure 25 unsuccessful attempt for a suitable allylic amination reaction employing the nucleophile as salt
After these two unsuccessful attempts using palladium as transition metal in catalysis, we decided to
focus on iridium based catalysts. Preferably we wanted to use a simple system applying cheap
ligands that were in stock. Therefore, we chose to modify a system developed by Takeuchi and coworkers. In this system [Ir(cod)Cl]2 was used as precatalyst and P(OPh)3 was employed as ligand
(figure 26). Now, also methyl cinnamyl carbonate was used as substrate instead of cinnamyl acetate.
But either no reaction took place, or again a complex mixture of products was yielded. It was
postulated that the catalyst was too sensitive for amino acids to be used as nucleophile.21
Figure 26 first attempt towards iridium catalyzed allylic amination
22
In 2010 Tosatti and co-workers published results of a allylic amination reaction employing polar
nucleophiles (amongst them were methyl esters of amino acids) in which methyl cinnamyl carbonate
was the substrate. In their methodology a relatively new precatalyst, [Ir(dbcot)Cl]2 (figure 27), is
used
instead
of
the
previously
mentioned
[Ir(cod)Cl]2.
This
precatalyst
based
on
dibenzo[a,e]cyclooctatetraene (dbcot) is much more stable than its original counterpart and the
formed active catalyst species, an iridacycle, is also less susceptible to hydrolysis and oxidation.22
Figure 27 dbcot and [Ir(dbcot)Cl]2
The dbcot ligand is not commercialy available and had to be prepared first. Several methods of
synthesizing this molecule have been developed, but only one of these routes proved to be
synthetically useful. In 2002 Wudl and co-workers published the synthesis of dbcot in an overall yield
of 49% over three steps (figure 28).23
The Wurtz coupling with two equivalents of α,α’-dibromo-o-xylene resulted in the product in
respectable yield, although a minor, inseperable, byproduct still remained present. Subsequent
dibromination cleanly resulted in the desired product. Results of the subsequent elimination were
not as satisfactory as reported by Wudl, but still synthetically useful.
Following a procedure by Singh et al. it was possible to synthesize [Ir(dbcot)Cl]2 in an overall yield of
23% over four steps.24
23
Figure 28 synthesis of [Ir(dbcot)Cl]2
With this precatalyst in hand we began reproducing the work by Tosatti. First, the active catalyst
species was formed by mixing [Ir(dbcot)Cl]2, a typical “Hartwig-type” ligand and some n-butylamine
to ensure formation. After 30 minutes of stirring at 55 °C the substrate (methyl cinnamyl carbonate),
the nucleophile (H-Ser-OMe·HCl), and a heterogenous base (K3PO4) were added (figure 29). With
these conditions Tosatti was able to obtain the desired branched product in 81% yield and with a dr
of 81:19 after eight hours of stirring at 55 °C. However, in our case there was no full conversion of
the substrate observed and the product’s mass was not detected in an LCMS experiment. After 48
hours there was still no full conversion of the substrate and no significant product formation,
however, all of the nucleophile was consumed.
Figure 29 asymmetric allylic amination as proposed by Tosatti
24
After several tests, in which either the solvent or the nucleophile was changed (results summarized
below, table 1) and no progress in product formation was observed, we postulated that the
heterogenous base was not functioning appropriately. In order to investigate this and exlude that
the basis of our apparent failure was the quality of the catalyst system, we wanted to test a wellknown reaction with an amine, which did not have to be liberated from its HCl salt. Additionally we
had to change the work-up procedure since we do not have sufficient equipment to evaporate
DMSO. Instead of simple evaporation of DMSO followed by column chromatography we chose to
dilute the reaction mixture with water and extract it with DCM after which column chromatography
should lead to pure isolated product. As nucleophile we chose aniline and indeed, we were now able
to isolate the product in sufficient yield.
Table 1 initial test results for AAA employing the conditions developed by Tosatti
LG
Nuc.
Solvent
Base
Mol% Ir
Yield %
OCO2Me
H-Ser-OMe·HCl
DMSO
K3PO4
2
nd
OCO2Me
H-Ala-OMe·HCl
DMSO
K3PO4
2
nd
OCO2Me
H-Ala-OMe·HCl
THF
K3PO4
2
nd
OCO2Me
Aniline
DMSO
Salt-free
2
64
It might be that the polycrystalline character of the heterogenous base K3PO4 was the problem.
Therefore, we might be able to improve the reaction by increasing the surface area of the base by
first crushing it. In this case we were able to observe some product after 48 hours, but still not
significant.
Since this was not desirable it was decided to switch to a homogenous base. Et3N was chosen as
base, however, the results were comparable to the initial test results. The outcome of these
reactions is depicted in table 2.
25
Table 2 AAA test results where the base is homogenous Et3N
LG
Nuc.
Solvent
Base
Mol% Ir
Yield %
OCO2Me
H-Ala-OMe·HCl
DMSO
Et3N
2
nd
OCO2Me
H-Phe-OMe·HCl
DMSO
Et3N
2
nd
OAc
H-Phe-OMe·HCl
DMSO
Et3N
2
nd
Thereafter, we chose to copy the conditions for the allylic amination with aniline as much as possible.
For this we needed to liberate the amine from its HCl salt prior to the reaction instead of liberating it
in situ. This is simply done by adding the HCl salt of the amino acid ester to a saturated aqueous
suspension of NaHCO3 and extracting this with ethyl acetate. In this way, however, one is restricted
to more apolar amino acids, otherwise the amino acid will stay in the aqueous phase. This is why,
from now on, the nucleophiles of choice are esters of phenylalanine. In solution the nucleophiles
might dimerize to diketopiperazines as was the case with H-Phe-OMe (table 3). In order to
circumvent this problem, we eventually chose the more stable tert-butyl ester of phenylalanine.
With a precatalyst loading of 2 mol% as stated by Tosatti, we were able to observe the anticipated
product after 24 hours, but not at full conversion. Even after 48 hours the substrate was not fully
converted (table 3). This is not only detrimental to the yield but also to the purity of the product.
Since the substrate has a similar retention time as the product on TLC they are inseparable. But by
doubling the precatalyst loading we were eventually able to get full conversion and able to isolate 55%
of product after 48 hours.
26
Table 3 optimized AAA test results
LG
Nuc.
Solvent
Base
Mol% Ir
Yield %
OCO2Me
H-Phe-OMe
DMSO
Salt-free
2
Product
OCO2Me
H-Phe-OBn
DMSO
Salt-free
2
nd
OCO2Me
H-Phe-Ot-Bu
DMSO
Salt-free
2
Product (24h)
OCO2Me
H-Phe-Ot-Bu
DMSO
Salt-free
2
Product (48h)
OCO2Me
H-Phe-Ot-Bu
DMSO
Salt-free
4
55 (48h)
With this optimized procedure cinnamyl acetate was also tested in the allylic amination reaction
with H-Phe-Ot-Bu as nucleophile. Even after 48 hours stirring of at 55 °C, however, no reaction took
place. The acetate group does not seem to be a sufficient leaving group in this type of allylic
amination reaction (figure 30).
Figure 30 unsuccessful attempt towards employment of cinnamyl acetate as substrate in allylic amination
27
Chapter 3 Synthesis of the Auxiliary
During the development of a suitable methodology for the allylic amination step we already started
synthesis of possible auxiliaries. This auxiliary has to have two functionalities. First, it should be able
to couple a peptide and second, it has to facilitate the previously developed allylic amination
procedure. We envisioned an auxiliary that bears a hydroxyl moiety in order to couple a peptide and
a allylic leaving group, such as in the cinnamyl derived test substrate, for the allylic amination
reaction (figure 31, A). Also substrates that bear a phenolic ortho-acetate were required. These can
be used as test substrates for the allylic amination/O-to-N acyl transfer cascade (figure 31, B). Both
methyl cinnamyl carbonates as well as cinnamyl acetates were synthesized.
Figure 31 auxiliaries (in red, A) and test substrates (in red, B) to be developed and their eventual use
Results
At first we performed a route in which the hydroxyl group of cis/trans 2-propenylphenol was first
protected with a TBS group (figure 32).26 Thereafter, we performed a Grubbs metathesis reaction
with cis-1,4-diacetoxy-2-butene to synthesize o-OTBS cinnamyl acetate.25 After deprotection we
would then be able to esterify the hydroxyl moiety. However, when we tried to perform the
metathesis reaction with the Grubbs second generation catalyst we were not able to obtain the
desired product in good yield and abandoned the route.
28
Figure 32 initially envisioned synthesis of o-OH cinnamyl acetate
The second methodology employed an allylic acyloxylation reaction after protection of the hydroxyl
group. First, the hydroxyl group of 2-allylphenol was acetylated or protected with a TBS group (figure
33).26 After this, an acyloxylation reaction with either acetic, or propionic acid was conducted to
form the leaving group. 27 Since propionate is not a common leaving group in the allylic amination
reaction, it was decided to focus the research on cinnamyl acetate derivatives.
Figure 33 allylic acyloxylation of ortho substituted allylbenzene derivatives
The palladium catalyzed acyloxylation reaction involving TBS protected alcohol was less efficient
when compared to the o-acetates, probably due to steric hindrance. The reaction is highly selective
towards the E-isomer in all cases. The o-acetate cinnamyl propionate could directly be used in a
allylic amination/O-to-N aycl transfer sequence. The TBS group of o-OTBS cinnamyl acetate and
propionate, however, first has to be cleaved off before the auxiliary can be further functionalized
with an amino acid or peptide (figure 34). Standard removal of the TBS group with TBAF resulted in
o-hydroxy cinnamyl acetate in good yield.28
Figure 34 deprotection of the phenolic hydroxyl group in the synthesis of o-OH cinnamyl acetate
29
Also attempts towards o-hydroxy methyl cinnamyl carbonate were made. Again the phenolic
hydroxyl group could, afterwards, be esterified in such a way that the auxiliary is suitable for use in
the allylic amination/O-to-N acyl-transfer sequence.
At first, the envisioned route employed protection of the alcohol with a TIPS group. Here
salicylaldehyde was reacted with a Wittig reagent to yield (E)-methyl 3-(2-hydroxyphenyl)acrylate
(figure 35).22 Although this reaction works well, after column chromatography there is still a
relatively large fraction, which is contaminated with the side-product triphenylphosphine oxide due
to partial crystallization on the column. This, however, is not a problem in the follow-up chemistry.
Thereafter, the hydroxyl group is protected with a TIPS group in excellent yield.29 This is then
followed by reduction of the methyl ester to the alcohol. The alcohol was then cleanly reacted to the
methyl carbonate using methyl chloroformate.30 After deprotection the molecule would be ready for
further functionalization towards the auxiliary.
Figure 35 synthesis of o-OTIPS methyl cinnamyl carbonate
30
Deprotection, however, proved to be rather difficult. Standard deprotection with TBAF resulted in a
complex mixture. A more mild deprotection employing KOAc was published by Wang and co-workers.
KOAc, did not result in deprotection in this system, though. Several acids such as NH4F and HClO4,
were tried in the deprotection, however, all of these attempts resulted in polymerization-like
products. With a basic fluoride source, pyridine hydrogen fluoride, no reaction took place. It was
postulated that the desired product might be too unstable; carbon dioxide might eliminate when
strong acidic removal is employed.
After several unsuccessful attempts towards the auxiliary in which we tried to avoid the use of
protecting groups we decided to replace TIPS for a THP group. This labile protecting group is, in
general, easily cleaved under mildly acidic conditions. The synthetic route was similar to the “TIPSroute” mentioned before, now only hydroxyl protection was conducted using the THP protecting
group. With pyridinium para-toluene sulfonate (PPTS) the hydroxyl moiety could be protected within
48 hours (figure 36).
The follow-up chemistry is again the same as in the previously illustrated methodology. Deprotection
occurs with PPTS in MeOH/DCM within 48 hours. However, the product is very unstable due to the
sensitive allylic carbonate and the acidic phenolic proton. Therefore, the crude product can never be
evaporated to dryness, otherwise the traces of acid will affect the molecule severely. On the other
hand, however, methanol should be evaporated before follow-up chemistry can be initiated.
Therefore, ethyl acetate has to be added to the crude product, in this way the crude mixture will not
get too concentrated when the methanol is being evaporated. In addition, evaporation of the
volatiles should always happen at room temperature since the product is unstable at higher
temperatures. The subsequent reaction is then performed in ethyl acetate.
Now the hydroxyl moiety has to be esterified for use in the allylic amination/acyl-transfer reaction.
The test substrate (o-OAc methyl cinnamyl carbonate) was synthesized by using an excess of acetyl
chloride (figure 36).
31
Figure 36 synthesis of o-OAc methyl cinnamyl carbonate
32
Chapter 4 Coupling of the Auxiliary to an Amino Acid
Below, the coupling of the auxiliary to an amino acid will be discussed. After coupling, the molecule
can be used in the allylic amination/O-to-N acyl-transfer cascade, which will be discussed in the next
chapter.
Results
For the ester bond formation between the auxiliary and a peptide or amino acid several
methodologies were investigated. At first, we focused on a coupling using HATU and Hunig’s base as
employed by Rutters in the coupling of 2-hydroxy-β-nitrostyrene since these systems are very similar
(figure 37).17 However, HATU did not prove to be the appropriate coupling reagent. Several attempts
were made with different amino acids but all coupling reactions resulted in complex mixtures. DCC
itself was not reactive enough, however, when DMAP was added as catalyst we were able to couple
the auxiliary and Boc-Phe-OH using DCC.17
Figure 37 the several attempts towards amide bond formation
To test if this process went without any epimerization we also synthesized the molecule in which the
nucleophile was racemic Boc-Phe-OH. In general coupling of an amino acid proceeds without
epimerization, which can easily be deduced from the mechanism for epimerization (figure 38).
Epimerizaton only takes place at a peptide C-terminus, not when an carbamate protected amino acid
is used as coupling partner. First, the coupling reagent (DCC) adds to the C-terminus of the peptide.
It now becomes a very good leaving group. The adjacent amino acid then attacks this C-terminus and
the leaving group is released under oxazolone formation. Due to tautomerism epimerization takes
place. After ring opening, the original tertiary carbon atom at the C-terminal amino acid is now
epimerized.31
33
Figure 38 mechanism of the epimerization accompanied with DCC coupling
By employing chiral HPLC measurements on both the optically pure and racemic compounds we
were able to determine if epimerization took place. The racemate gives two peaks of similar height
where the expected enantiopure compound shows only one (figure 39). This indicates that indeed
no epimerization took place.
uV
Figure 39 HPLC diagrams of racemic (left) and optically pure (right) coupling products (1 PDA Multi 1 / 254nm 4nm)
34
Chapter 5 Testing the Allylic Amination/Acyl-transfer Sequence
The next step towards peptide cyclization is testing the Allylic amination/O-to-N acyl-transfer
cascade reaction with o-OAc methyl cinnamyl carbonate as substrate, since allylic amination with oOAc cinnamyl acetate was unsuccessful (figure 40). Results are summed-up below.
Figure 40 the envisioned test allylic amination/O-to-N Acyl transfer reaction
Results
With the new allylic amination methodology and the auxiliaries in hand we could now test if the Oto-N acyl-transfer would take place with the ortho-acetate auxiliary (o-OAc methyl cinnamyl
carbonate). A first attempt, using the optimized conditions, failed because, since even after three
days of stirring, we could still not observe full conversion of the auxiliary. Therefore, we increased
the amount of catalyst to 12 mol%. In this case we got full conversion after the previously
established time (48 hours). However, we were not able to observe the desired product, the allylic
amination product wherein the acetate migrated to the nitrogen atom. Instead we observed six new
products of which four were isolatable (figure 41). All products were obtained in minimum yield.
Figure 41 results of the first allylic amination, O-to-N acyl-transfer sequence
35
Two products arose from the attack of methoxide on the allyl system. Methoxide is released when
carbonate splits of as leaving group and disintegrates to carbon dioxide and methoxide. The
products were o-OAc cinnamyl methyl ether and o-OH cinnamyl methyl ether. Two striking features
are observed. First, in one of the products the acetate has split off and second, the linear isomer is
formed in the allylic etherification instead of the branched isomer, which is the product we would
expect for the allylic amination reaction. The acetate is cleaved off probably because the acyltransfer is much faster than the allylic amination reaction so another molecule of phenylalanine tbutyl ester has taken up the acetyl group intermolecularly. Also, the regioselectivity of the reaction is
such that the methoxide attacks in such a way that the linear isomer is formed, which, in general, is
the minor product in the allylic substitution reaction with a small oxygen nucleophile. This is difficult
to explain, however, we propose the following (figure 42). First, the oxygen of the carboxyl group
attacks on the benzylic position, hereby this position is blocked. This unstable intermediate then
decomposes to the linear isomer by attack of methoxide.
Figure 42 postulated explanation for attack of methoxide towards the linear product
There were two more products isolated. One of these is the apparent product of allylic amination of
the nucleophile at the benzylic position. However, again the acetate group is cleaved off from the
oxygen atom and did not migrate to nitrogen and furthermore, the reaction proceeded without
enantioselective control. Since the catalyst environment is asymmetric and earlier experiments
yielded a enantiopure product it might be that the product is not made via this allylic amination
pathway, but through a completely different pathway.
The final product, which was isolated was unidentified since its 1H-NMR spectrum displayed only
very broad peaks. This might be some sort of polymer kept together with hydrogen bonds.
36
Conclusion and Outlook
The goal of this project was to develop a methodology, which employs a sequence of allylic
amination and O-to-N acyl-transfer in order to synthesize cyclic peptides.
The first goal, development of an appropriate allylic amination reaction procedure, was achieved
after careful re-examination of an article by Tosatti and co-workers. Where this group employes a
heterogenous base in order to free an amino acid methyl ester in situ, we had to adjust the system in
such a way that salt-free conditions are met since K3PO4 could not be employed. Additionally, the
molar percentage of catalyst had to be doubled to fully convert the starting methyl cinnamyl
carbonate. As nucleophile we employed, the more stable tert-butyl ester of phenylalanine, which
was first freed from its hydrochloric acid salt. When cinnamyl acetate was used as substrate no
conversion towards the product was observed.
The next target was to synthesize the auxiliary. We developed both auxiliaries bearing a acetate
leaving group as well as a carbonate leaving group. However, allylic amination employing substrates
bearing a acetate leaving group did not succeed. Therefore, the focus was primarily set to the
synthesis of o-OH methyl cinnamyl carbonate. When this molecule would be synthesized we would
be able to create libraries of test substrates and auxiliaries for employment in the allylic
amination/acyl-transfer sequence. After several attempts we were able to synthesize this auxiliary.
The molecule itself proved to be very sensitive to temperature and an acidic environment, which
made handling difficult. Therefore, we had to do follow-up chemistry without isolation of the this
auxiliary. Eventually, we were able to synthesize o-OAc methyl cinnamyl carbonate, which could be
used as test substrate in the allylic amination/acyl-transfer sequence.
Additionally we were able to develop a epimerization free methodology to couple amino acids to the
cinnamyl acetate derived auxiliary by using DCC and DMAP.
The test auxiliary (o-OAc methyl cinnamyl carbonate) was used in the allylic amination/acyl-transfer
cascade with H-Phe-Ot-Bu. At first, no full conversion was observed. But after increasing the molar
percentage of precatalyst to 12% we were able achieve full conversion. However, none of the
isolated products turned out to be the desired molecule that had undergone O-to-N acyl-transfer
after allylic aminaton. The problem is probably the reaction rate of the allylic amination reaction
when compared to the acyl-transfer. The acyl-transfer is much faster and happens intermolecularly
before, instead of, intramolecularly after the allylic aminaton reaction.
37
In order to speed up the allylic aminaton reaction adjustments should be made to the substrate.
However, cinnamyl derived substrates are, in general, the most efficient substrates for this reaction,
since they enhance both rate and regioselectivity. One could use a substrate where the phenyl ring is
replaced by a small alkane chain, but this would make regioselective control almost impossible and
there would be a lot of flexibility which makes it difficult to bring both peptide termini in close
proximity (figure 43, A).32 Another change could be replacement of the phenyl ring by a furan ring
which, in some cases enhance the reaction rate (figure 43, B).33 Further functionalization of this
furan derived molecule is rather difficult due to keto-enol tautomerization. Therefore, employment
of this strategy towards the synthesis of cyclic peptides seems to be futile.
Figure 43 expected issues when the phenyl group in the auxiliary is replaced by either an alkyl chain or a furan ring
38
Acknowledgments
Five and half year ago I started my studies here at the university of Amsterdam. During my high
school years I realized I was destined to study chemistry. I had a special interest for toxicology when
I started at the university. But I soon found out that this subject has a few aspects that I am simply
not that fond of. What made me change my mind?
Mainly my inherent interest in creating things. This started when I was young; at five I got my first
Lego-train, I could not be happier at that time. This is still clearly visible in my choice for synthetic
chemistry.
But another, very important, factor was Jan. From day one this cross-eyed nutty professor inspired
me. His enthusiasm has no limits and combined with his keen sense for education and research this
makes him a great academician. I really love the way you can present chemistry with a smile. You
really deserve the price for “Docent van het Jaar”, congratulations and I am especially grateful to you
for showing me the beauty of this field of chemistry.
After a few projects at the group of Joost Reek, who earns a big thank you for giving me the
opportunity to experience metal-organic chemistry on a practical level, I started my Bachelor project
at the Synthetic Organic Chemistry group. Jan and Henk, thank you for that. Although the endproduct could have been better they still accepted me to do yet another big project at this group:
my Master project.
I have been here for over a year now and very much enjoyed my stay here. Not everything went
according to plan, but this is (chemistry)life. I’m going to miss the Oranjekoek and Serbian calorie
bombs, mister Fukuyama (better known as FockYoMamma) during meetings, everyone I have played
cards with during breaks, fighting over the radio and just my everyday life here in the lab.
Thanks again Henk and Jan for giving me this opportunity. Thank you Kees and Remko for being my
second supervisors. A special thank you goes out to Luuk, Berend and Nick for flanking me in the lab,
I have had great times there. I want to thank Patrick Bart for doing a language and spelling check on
my thesis and of course the rest of the group for helping me with all kinds of stuff!
THANKS ALL!
39
Experimental section
Synthesis of this compound was based on a procedure by Ohkoshi and co-workers.30
In a flame-dried round-bottomed flask under N2, cinnamyl alcohol (2.0 g, 14.9 mmol, 1 equivalent)
and pyridine (1.3 g, 16.4 mmol, 1.1 equivalents) were dissolved in anhydrous DCM (60 ml). Then the
mixture was cooled down to 0 °C and methyl chloroformate (2.5 g, 26.9 mmol, 1.8 equivalents) was
added dropwise. The mixture was then stirred for two hours at room temperature, 1 M HCl was
added and the mixture was extracted with dichloromethane. After drying and purification by column
chromatography methyl cinnamyl carbonate was obtained as a yellow oil (2.6 g, 13.5 mmol, 91%). 1H
NMR (400 MHz, CDCl3) δ 7.50 – 7.38 (m, 2H), 7.41 – 7.31 (m, 2H), 7.34 – 7.23 (m, 1H), 6.72 (d, J =
15.8 Hz, 1H), 6.33 (dt, J = 15.9, 6.4 Hz, 1H), 4.82 (dt, J = 6.5, 0.9 Hz, 2H), 3.83 (s, 3H).30
Synthesis of these compounds was based on a procedure by Chaffins and co-workers.23
In a flame-dried round-bottomed flask under Ar at 0 °C, α,α’-dibromo-o-xylene (4.0 g, 15.1 mmol, 1
equivalent) was added carefully to a dispersion of cut up lithium granules (631 mg, 91.0, 6
equivalents) in anhydrous THF (20 ml). The system was then equipped with a condenser and
sonicated overnight at room temperature. The mixture was then cooled down to 0 °C, carefully
quenched with ice-cold water, extracted with Et2O, dried and purified by column chromatography to
yield 5,6,11,12-tetrahydrodibenzo[a,e][8]annulene as a white powder (1.07 g, 5.14 mmol, 68%).1H
NMR (400 MHz, CDCl3) δ 7.37 (dd, J = 5.5, 3.4 Hz, 1H), 7.28 (t, 1H), 7.09 – 6.95 (m, 8H), 3.09 (s, 8H),
3.08 (s, 2H).23
40
Synthesis of these compounds was based on a procedure by Chaffins and co-workers.23
In a flame-dried round-bottomed flask under N2, 5,6,11,12-tetrahydrodibenzo[a,e][8]annulene (2.00
g, 9.62 mmol, 1 equivalent) was dissolved in anhydrous CCl4 (50 ml) and NBS (3.42 g, 19.2 mmol, 2
equivalents) was added. The mixture was then refluxed for two hours, cooled to room temperature
and filtrated to remove the solid succinimide. The solvent was then removed in vacuo and the solid
mass was washed with water to yield 5,11-dibromo-5,6,11,12-tetrahydrodibenzo[a,e][8]annulene
(3.50 g, 9.56 mmol, 99%).1H NMR (400 MHz, CDCl3) δ 7.13 (td, J = 7.3, 1.5 Hz, 2H), 7.10 – 7.02 (m, 4H),
6.97 (dd, J = 7.6, 1.4 Hz, 2H), 5.34 (dd, J = 11.2, 8.5 Hz, 2H), 4.29 (dd, J = 14.2, 11.2 Hz, 2H), 3.66 (dd, J
= 14.2, 8.5 Hz, 2H).23
Synthesis of these compounds was based on a procedure by Chaffins and co-workers.23
In a flame-dried round-bottomed flask under N2 at 0 °C, a solution of 5,11-dibromo-5,6,11,12tetrahydrodibenzo[a,e][8]annulene (1.00 g, 2.73 mmol, 1 equivalent) in anhydrous THF (25 ml) was
slowly added to a dispersion of 0.72 M KOt-Bu in anhydrous THF (60 ml) and the mixture was then
stirred overnight at room temperature. The mixture was carefully quenched with water and
extracted with chloroform. The combined organic phases were dried and purified by column
chromatography to yield dibenzo[a,e]cyclooctatetraene (241 mg, 1.18 mmol, 43%).1H NMR (400
MHz, CDCl3) δ 7.20 – 7.11 (m, 4H), 7.11 – 7.01 (m, 4H), 6.75 (s, 4H).23
[Ir(dbcot)Cl]2
Synthesis of these compounds was based on a procedure by Singh and co-workers.24
In a flame-dried round-bottomed flask under N2, dbcot (91.0 mg, 0.45 mmol, 3 equivalents) was
dissolved in anhydrous DCM (5 ml), subsequently a solution of [Ir(cod)Cl]2 (100 mg 0.15 mmol, 1
equivalent) in anhydrous DCM (5 ml) was added. This mixture was stirred for one hour at room
temperature and concentrated to circa 5 ml. Et2O (10 ml) was added and the mixture was then
stored at -30 °C for 24 hours and filtered to yield [Ir(dbcot)Cl]2 as a yellow solid (103 mg, 0.12 mmol,
79%). 1H NMR (300 MHz, CD2Cl2) δ 7.15 – 7.00 (m, 4H), 7.00 – 6.87 (m, 4H), 5.40 (s, 4H).24
41
General procedure for the allylic amination
In a small capped vial, [Ir(dbcot)Cl]2 (4.50 mg, 0.005 mmol, 4 mol%) N,N-bis[(1S)-1phenylethyl]dinaphtho[2,1-d:1,2-f][1,3,2]dioxaphosphepin-4-amine (5.90 mg, 0.011 mmol, 8 mol%)
and n-butylamine (1.07 μl, 0.011 mmol, 8 mol%) were dissolved in DMSO (1 ml) and stirred for 30
minutes at 50 °C. Thereafter, the substrate or auxiliary (0.13 mmol, 1 equivalent) and the
nucleophile (0.39 mmol, 3 equivalents) were added and the solution was stirred for 48 hours at 50 °C.
Subsequent addition of DCM was followed by washing with water. After column chromatography
the respective allylamine was obtained.
Colorless oil (64%) 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.38 (m, 4H), 7.38 – 7.28 (m, 1H), 7.25 – 7.15
(m, 2H), 6.76 (tt, J = 7.3, 1.1 Hz, 1H), 6.68 – 6.64 (m, 2H), 6.10 (ddd, J = 17.1, 10.2, 5.9 Hz, 1H), 5.33
(dt, J = 24.4, 1.4 Hz, 1H), 5.30 (dt, J = 17.4, 1.4 Hz, 1H), 5.00 (dt, J = 5.9, 1.4 Hz, 1H), 4.09 (s, 1H).34
Colorless oil (55%) 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.13 (m, 10H), 5.92 (ddd, J = 17.1, 10.1, 7.1 Hz,
2H), 5.18 (dt, J = 17.1, 1.3 Hz, 2H), 5.06 (dt, J = 10.1, 1.2 Hz, 2H), 4.21 (d, J = 7.2 Hz, 2H), 3.26 (t, J =
7.0 Hz, 2H), 2.91 (d, J = 7.0 Hz, 4H), 2.03 (s, 1H), 1.40 (s, 18H). 13C NMR (101 MHz, CDCl3) δ 173.95,
141.78, 141.07, 137.68, 129.67, 128.56, 128.22, 127.67, 127.38, 126.56, 115.17, 81.25, 64.52, 60.44,
40.10, 28.15.
42
Synthesis of this compound was based on a procedure by Gresser and co-workers. 35
In a round-bottomed flask, a solution of acetic anhydride (25 ml, 265 mmol, 35.6 equivalents), 2allylphenyl acetate (1.0 g, 7.45 mmol, 1 equivalent) and triethylamine (25 ml, 179 mmol, 24.0
equivalents) was stirred for 24 hours at room temperature. The mixture was then quenched with
water and extracted with dichloromethane. The combined organic phases were washed with 1 M
sodium hydroxide, dried and purified by column chromatography to yield o-OAc allylbenzene as
colorless oil (1.21 g, 6.87 mmol, 92%). 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.21 (m, 2H), 7.21 – 7.12 (m,
1H), 7.05 (dd, J = 8.1, 1.4 Hz, 1H), 6.01 – 5.82 (m, 1H), 5.10 (hept, J = 2.1 Hz, 1H), 5.06 (dp, J = 5.4, 1.7
Hz, 1H), 3.32 (dt, J = 6.6, 1.6 Hz, 2H), 2.29 (s, 3H).35
Synthesis of this compound was based on a procedure by Kondo and co-workers.26
In a round-bottomed flask at 0 °C, 2-allylphenol (5.0 g, 37.3 mmol, 1 equivalent), TBSCl (6.1 g, 40.3
mmol, 1.08 equivalents) and imidazole (7.0 g, 103 mmol, 2.75 equivalents) were dissolved in DMF
(50 ml) and the solution was stirred for one hour at 0 °C, diluted with water and extracted with
EtOAc. The combined organic phases were then subsequently washed with brine, dried and purified
by column chromatography to yield o-OTBS allylbenzene as colorless oil (8.2 g, 33.1 mmol, 89%). 1H
NMR (400 MHz, CDCl3) δ 7.27 (dd, J = 7.2, 1.9 Hz, 1H), 7.21 (tt, 1H), 7.02 (tt, J = 7.4, 1.6 Hz, 1H), 6.94
(dd, J = 8.0, 1.5 Hz, 1H), 6.20 – 6.04 (m, 1H), 5.23 – 5.13 (m, 2H), 3.56 – 3.49 (m, 2H), 1.20 – 1.14 (m,
9H), 0.38 (d, J = 2.3 Hz, 6H).35
43
General procedure for the acyloxylation
Synthesis of these compounds was based on a procedure by Thiery and co-workers.27
In a round-bottomed flask , LiOH·H2O (4.0 mmol, 2 equivalents) was dissolved in the specific acid (4
ml) by stirring at 40 °C for ten minutes, subsequently p-benzoquinone (4.0 mmol, 2 equivalents),
Pd(OAc)2 (0.20 mmol, 0.1 equivalents) and another equivalent of the acid (4 ml) were added and the
mixture was stirred for 15 minutes at room temperature. Ortho substituted allylbenzene (2.0 mmol,
1 equivalent) was then added and the mixture was further stirred for 24 hours at 40 °C. The mixture
was allowed to cool down to room temperature, filtered over a silica pad and washed with Et2O.
Hereafter, a 2 M solution of sodium hydroxide was added and the mixture was stirred for 15 minutes
at room temperature. The organic phase was then washed with water and the combined aqueous
phases were subsequently washed with Et2O. The combined organic phases were dried and purified
by column chromatography to obtain the ortho substituted cinnamyl ester.
Yellowish oil (57%) 1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 7.7, 1.7 Hz, 1H), 7.14 (ddd, J = 8.1, 7.3,
1.8 Hz, 1H), 7.00 (dt, J = 16.2, 1.5 Hz, 1H), 6.93 (td, J = 7.5, 1.2 Hz, 1H), 6.80 (dd, J = 8.2, 1.2 Hz, 1H),
6.24 (dt, J = 16.1, 6.2 Hz, 1H), 4.75 (dd, J = 6.2, 1.5 Hz, 2H), 2.38 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz,
3H), 1.04 (s, 9H), 0.22 (s, 6H).
Yellowish oil (53%) 1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 7.8, 1.8 Hz, 1H), 7.14 (ddd, J = 8.2, 7.3,
1.8 Hz, 1H), 6.99 (dt, J = 16.0, 1.5 Hz, 1H), 6.93 (td, J = 7.5, 1.4 Hz, 1H), 6.80 (dd, J = 8.1, 1.2 Hz, 1H),
6.23 (dt, J = 16.0, 6.2 Hz, 1H), 4.74 (dd, J = 6.2, 1.5 Hz, 2H), 2.10 (s, 3H), 1.03 (s, 9H), 0.22 (s, 6H).25
Yellowish oil (75%) 1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 7.8, 1.7 Hz, 1H), 7.27 (td, J = 7.7, 1.7 Hz,
1H), 7.19 (td, J = 7.5, 1.4 Hz, 1H), 7.04 (dd, J = 8.0, 1.4 Hz, 1H), 6.67 (dt, J = 16.0, 1.5 Hz, 1H), 6.29 (dt,
J = 16.0, 6.3 Hz, 1H), 4.72 (dd, J = 6.3, 1.4 Hz, 2H), 2.37 (q, J = 7.6 Hz, 2H), 2.32 (s, 3H), 1.16 (t, J = 7.6
Hz, 3H).
44
General procedure for the deprotection of the alcohol after the acycloxylation reaction
Synthesis of these compounds was based on a procedure by Kobayashi and co-workers.28
In a flame-dried round-bottomed flask under N2, o-OTBS cinnamyl ester (3.12 mmol, 1 equivalent)
was dissolved in anhydrous THF (25 ml) and the mixture was cooled down to 0 °C. A solution of 1 M
TBAF in THF (3.12 mmol, 1 equivalent) and the mixture was stirred for one hour at room
temperature. The mixture was then diluted with aqueous saturated NH4Cl and extracted with EtOAc.
After washing the combined organic phases with water and brine the crude product was purified by
column chromatography to obtain the o-OH cinnamyl ester.
Colorless oil (92%) 1H NMR (400 MHz, CDCl3) δ 7.38 (dd, J = 7.7, 1.7 Hz, 1H), 7.13 (ddd, J = 8.1, 7.4,
1.7 Hz, 1H), 6.97 – 6.85 (m, 2H), 6.80 (dd, J = 8.0, 1.2 Hz, 1H), 6.32 (dt, J = 16.0, 6.5 Hz, 1H), 6.11 (s,
1H), 4.75 (dd, 2H), 2.11 (s, 3H).36
Colorless oil (99%) 1H NMR (400 MHz, CDCl3) δ 7.40 (dd, J = 7.7, 1.7 Hz, 1H), 7.21 – 7.11 (m, 1H), 6.96
– 6.89 (m, 2H), 6.81 (dd, J = 8.1, 1.1 Hz, 1H), 6.34 (dt, J = 16.0, 6.4 Hz, 1H), 5.40 (s, 1H), 4.78 (dd, J =
6.5, 1.4 Hz, 2H), 2.41 (q, J = 7.5 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H).
Synthesis of these compounds was based on a procedure by Tosatti and co-workers.22
In a round-bottomed flask, salicylaldehyde (8.0 g, 0.066 mol, 1 equivalent) was dissolved in toluene
(150 ml), methyl-(triphenylphosphoranylidene)acetate (24.1 g, 0.072 mol, 1.1 equivalents) was
added and the mixture was refluxed for 48 hours. Subsequently, the mixture was allowed to cool to
room temperature, quenched with water and extracted with Et2O. The combined organic phases
were then washed with brine, dried and purified by column chromatography to yield o-hydroxy
methyl cinnamate as a white solid (5.26 g, 0.029 mol, 45%). 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J =
16.1 Hz, 1H), 7.50 (dd, J = 7.8, 1.7 Hz, 1H), 7.32 – 7.20 (m, 1H), 6.96 (td, J = 7.6, 1.1 Hz, 1H), 6.87 (dd, J
= 8.0, 1.0 Hz, 1H), 6.65 (d, J = 16.2 Hz, 1H), 6.19 (s, 1H), 3.85 (s, 3H).22
45
Synthesis of these compounds was based on a procedure by Ito and co-workers.
37
In a flame-dried round-bottomed flask under N2, o-hydroxy methyl cinnamate (1.5 g, 8.4 mmol, 1
equivalent) and (1.57 g, 23.1 mmol, 2.75 equivalents) were dissolved in anhydrous DMF (15 ml). The
mixture was cooled to 0 °C and TIPSCl (2.43 g, 12.6 mmol, 1.5 equivalents) was carefully added after
which the mixture was stirred for two hours at room temperature. Subsequently the mixture was
diluted with water and extracted with EtOAc. Hereafter, the combined organic phases were washed
with brine, dried and purified by column chromatography to yield o-OTIPS methyl cinnamate as a
colorless oil (2.53 g, 7.6 mmol, 90%). 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 16.2 Hz, 1H), 7.53 (dd, J
= 7.7, 1.8 Hz, 1H), 7.23 (ddd, J = 8.4, 7.3, 1.8 Hz, 1H), 6.94 (td, J = 7.6, 1.2 Hz, 1H), 6.85 (dd, J = 8.2, 1.2
Hz, 1H), 6.40 (d, J = 16.2 Hz, 1H), 3.79 (s, 3H), 1.40 – 1.24 (m, 3H), 1.13 (d, J = 7.4 Hz, 18H).
In a flame-dried round-bottomed flask under N2, o-OTIPS methyl cinnamate (2.2 g, 6.58 mmol, 1
equivalent) was dissolved in anhydrous DCM (20 mL) and cooled to -78 °C. A separate flame-dried
round-bottomed flask under N2 at -78 °C was loaded with 1 M dibal-H in toluene (19.7 ml, 19.7 mmol,
3 equivalents). When both solutions were cooled to -78 °C, the dibal-H solution was added dropwise
to the solution of o-TIPS methyl cinnamate and stirred for 20 minutes at -78 °C. Subsequently, the
acetone/dry-ice bath was removed and 40 ml of Rochelle’s salt was carefully added during which the
solution is allowed to heat up to room temperature. The mixture was then stirred at room
temperature for four hours after which the mixture was extracted with DCM. The combined organic
phases were then dried to yield o-OTIPS cinnamyl alcohol as colorless oil (1.92 g, 6.26 mmol, 95%).
1
H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 7.8, 1.8 Hz, 1H), 7.17 – 7.05 (m, 2H), 6.90 (td, J = 7.6, 1.2 Hz,
1H), 6.81 (dd, J = 8.1, 1.1 Hz, 1H), 6.24 (dt, J = 16.0, 6.4 Hz, 1H), 4.80 (dd, J = 6.5, 1.4 Hz, 2H), 1.39 –
1.23 (m, 3H), 1.11 (d, J = 7.5 Hz, 18H).
46
Synthesis of these compounds was based on a procedure by Ohkoshi and co-workers.30
In a flame-dried round-bottomed flask under N2, o-OTIPS cinnamyl alcohol (1.8 g, 5.87 mmol, 1
equivalent) and pyridine (0.95 ml, 11.74 mmol, 2 equivalents) were dissolved in anhydrous DCM (20
ml) and cooled to 0 °C. Methyl chloroformate (0.91 ml, 11.74 mmol, 2 equivalents) was added
dropwise and the solution was stirred overnight at room temperature. Subsequently, saturated
aqueous NH4Cl was added and the mixture was extracted with DCM after which the combined
organic phases were dried to yield o-OTIPS cinnamyl carbonate as a colorless oil (2.02 g, 5.54 mmol,
94%). 1H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 7.8, 1.8 Hz, 1H), 7.15 – 7.06 (m, 2H), 6.90 (td, J = 7.6,
1.3 Hz, 1H), 6.81 (dd, J = 8.1, 1.2 Hz, 1H), 6.24 (dt, J = 16.0, 6.4 Hz, 1H), 4.80 (dd, J = 6.5, 1.3 Hz, 2H),
3.80 (s, 3H), 1.37 – 1.23 (m, 3H), 1.12 (s, 18H).
In a flame-dried round-bottomed flask under N2, o-hydroxy methyl cinnamate (4.0 g, 0.022 mol, 1
equivalent), 3,4-dihydro-2H-pyran (8.2 ml, 0.090 mol, 4 equivalents) and pyridinium ptoluenesulfonate (1.13 g, 0.0045 mol, 0.2 equivalents) were dissolved in anhydrous DCM (80 ml).
The solution was stirred at room temperature for 48 hours. Subsequently NaHCO3 was added and
the mixture was extracted with DCM after which the combined organic phases were washed with
brine. Thereafter, the combined aqueous phases were extracted with DCM. Subsequent drying and
purification of the organic phases yielded o-OTHP methyl cinnamate as a colorless oil (5.32 g, 0.020
mol, 92%). 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 16.1 Hz, 1H), 7.52 (dd, J = 7.7, 1.8 Hz, 1H), 7.31
(ddd, J = 8.8, 7.3, 1.7 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 6.98 (t, J = 7.3 Hz, 1H), 6.55 (d, J = 16.1 Hz, 1H),
5.52 (t, J = 3.1 Hz, 1H), 3.85 (td, J = 11.0, 3.2 Hz, 1H), 3.80 (s, 3H), 3.65 – 3.56 (m, 1H), 2.14 – 1.80 (m,
2H), 1.81 – 1.48 (m, 4H).38
47
In a flame-dried round-bottomed flask under N2, o-OTHP methyl cinnamate (4.5 g, 0.017 mol, 1
equivalent) was dissolved in anhydrous DCM (50 mL) and cooled to -78 °C. A separate flame-dried
round-bottomed flask under N2 at -78 °C was loaded with 1 M dibal-H in toluene (57.2 ml, 0.057 mol,
3.4 equivalents). When both solutions were cooled to -78 °C, the dibal-H solution was added
dropwise to the solution of o-OTHP methyl cinnamate and stirred for 20 minutes at -78 °C.
Subsequently, the acetone/dry-ice bath was removed and 100 ml of Rochelle’s salt was carefully
added during which the solution is allowed to heat up to room temperature. The mixture was then
stirred at room temperature for four hours after which the mixture was extracted with DCM. The
combined organic phases were then dried to yield o-OTHP cinnamyl alcohol as colorless oil (3.98 g,
0.017 mol, 99%). 1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 7.6, 1.7 Hz, 1H), 7.20 (ddd, J = 8.8, 7.2, 1.7
Hz, 1H), 7.12 (dd, J = 8.4, 1.2 Hz, 1H), 7.01 – 6.91 (m, 2H), 6.40 (dtd, J = 16.1, 6.0, 1.7 Hz, 1H), 5.45 (t,
J = 3.3 Hz, 1H), 4.33 (dd, J = 5.9, 1.6 Hz, 2H), 3.89 (ddt, J = 14.9, 10.9, 3.9 Hz, 1H), 3.68 – 3.40 (m, 1H),
2.15 – 1.47 (m, 8H).38
Synthesis of these compounds was based on a procedure by Ohkoshi and co-workers.30
In a flame-dried round-bottomed flask under N2, o-OTHP cinnamyl alcohol (3.9 g, 0.017 mol, 1
equivalent) and pyridine (2.7 ml, 0.033 mol, 2 equivalents) were dissolved in anhydrous DCM (60 ml)
and cooled to 0 °C. Methyl chloroformate (2.6 ml, 0.033 mol, 2 equivalents) was added dropwise and
the solution was stirred overnight at room temperature. Subsequently, saturated aqueous NH4Cl
was added and the mixture was extracted with DCM after which the combined organic phases were
dried to yield o-OTHP cinnamyl carbonate as a colorless oil (4.8 g, 0.016, 97%). 1H NMR (400 MHz,
CDCl3) δ 7.45 (dd, J = 7.6, 1.7 Hz, 1H), 7.21 (ddd, J = 8.9, 7.2, 1.7 Hz, 1H), 7.12 (dd, J = 8.3, 1.2 Hz, 1H),
7.04 (dt, J = 16.0, 1.4 Hz, 1H), 6.95 (td, J = 7.5, 1.2 Hz, 1H), 6.34 (dt, J = 16.0, 6.6 Hz, 1H), 5.46 (t, J =
3.2 Hz, 1H), 4.81 (dd, J = 6.6, 1.3 Hz, 2H), 3.95 – 3.83 (m, 1H), 3.80 (s, 3H), 3.61 (dtd, J = 11.4, 4.0, 1.3
Hz, 1H), 2.09 – 1.50 (m, 8H).
48
In a flame-dried round-bottomed flask under N2, o-OTHP cinnamyl carbonate (100 mg, 0.34 mmol, 1
equivalent) and pyridinium p-toluenesulfonate (25.1 mg, 0.10 mmol, 0.3 equivalent) were dissolved
in anhydrous DCM/MeOH (50:50, 20 ml) and stirred at room temperature for 48 hours. EtOAc was
added (10 ml) and DCM and MeOH were carefully evaporated at room temperature. This process
was repeated three times to ensure complete evaporation of MeOH. Pyridine (5 ml) and acetyl
chloride (5 ml) were added dropwise at 0 °C. The mixture was then stirred under N2, overnight at
room temperature. Thereafter, 0.1 M HCl was added and the mixture was extracted with EtOAc.
Subsequently, the combined organic phases were washed with aqueous saturated NaHCO3 and
water, dried and purified by column chromatography to yield o-OAc cinnamyl carbonate as a
colorless oil (12.0 mg, 0.05 mmol, 14%). 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 7.7, 1.7 Hz, 1H),
7.30 (td, J = 7.7, 1.7 Hz, 1H), 7.21 (td, J = 7.4, 1.2 Hz, 1H), 7.05 (dd, J = 8.0, 1.3 Hz, 1H), 6.72 (dt, J =
15.9, 1.4 Hz, 1H), 6.30 (dt, J = 16.0, 6.4 Hz, 1H), 4.78 (dd, J = 6.4, 1.4 Hz, 2H), 3.81 (s, 3H), 2.34 (s, 3H).
1
H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 7.7, 1.7 Hz, 1H), 7.30 (td, J = 7.7, 1.7 Hz, 1H), 7.21 (td, J = 7.4,
1.2 Hz, 1H), 7.05 (dd, J = 8.0, 1.3 Hz, 1H), 6.72 (dt, J = 15.9, 1.4 Hz, 1H), 6.30 (dt, J = 16.0, 6.4 Hz, 1H),
4.78 (dd, J = 6.4, 1.4 Hz, 2H), 3.81 (s, 3H), 2.34 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.52, 155.86,
148.39, 129.37, 128.95, 128.38, 127.28, 126.51, 125.27, 122.97, 68.59, 55.16, 21.23.
49
In a flame-dried round-bottomed flask under N2, DCC (128 mg, 0.62 mmol, 1.2 equivalents)and BocPhe-OH (165 mg, 0.62 mmol, 1.2 equivalents) were dispersed in anhydrous DCM (5 ml) and cooled to
0 °C. A solution of o-OH cinnamyl acetate (100 mg, 0.52 mmol, 1 equivalent) and DMAP (32 mg, 0.26
mmol, 0.5 equivalent) in DCM (2 ml) was added and the mixture was first stirred at 0 °C for an hour
after which it was stirred overnight at room temperature. The mixture was then diluted with DCM,
washed with 1 M HCl, aqueous saturated NaHCO3 and water. After drying and column
chromatography of the combined organic phases the product could be obtained as a yellowish oil
(160 mg, 0.36 mmol, 70%). 1H NMR (400 MHz, CDCl3) δ 7.57 (dd, J = 7.6, 1.9 Hz, 1H), 7.41 – 7.18 (m,
6H), 6.92 (d, J = 7.8 Hz, 1H), 6.70 (d, J = 16.0 Hz, 1H), 6.29 (dt, J = 15.9, 6.3 Hz, 1H), 5.10 (d, J = 7.7 Hz,
1H), 4.87 (q, J = 6.9 Hz, 1H), 4.72 (dd, J = 6.5, 1.5 Hz, 2H), 3.37 – 3.19 (m, 2H), 2.09 (s, 3H), 1.46 (s, 9H).
50
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51