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Page 1: Abstract - UvA · Web view-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

OCO2Me

OH

HO2C

NHPG

HO2C NHPGLG

OH

NHO

HO2C NHPGLG

OH

NHO

Towards Auxiliary Mediated Peptide Cyclization Employing an Allylic Amination/Acyl-Transfer Cascade Reaction

Master Thesis Sjoerd SlagmanHIMS, Synthetic Organic Chemistry (SOC), FNWI, UvAFirst supervisor Dr. Jan van MaarseveenSecond supervisor Prof. Kees ElsevierProfessor Prof. Henk Hiemstra

Δ

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AbstractSmall 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.

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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)

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List of AbbreviationsAA Amino acidAAA Asymmetric allylic aminationAc AcetylAla AlanineAlk AlkylArg ArginineAsp Aspartic acidBn BenzylBoc Tert-butyl carbonateBt 1H-Benzo[d][1,2,3]triazol-1-ylBu Butylc CycloCat. Catalystcod 1,5-CyclooctadieneConv. ConversionD Aspartic acidd Doubletdbcot Dibenzo[a,e]cyclooctatetraeneDCC N,N’-DicyclohexylcarbodiimideDCM DichloromethaneDEPBT 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-oneDIBAL-H Diisobutylaluminium hydrideDIPEA N,N-DiisopropylethylamineDMAP 4-DimethylaminopyridineDMSO Dimethyl sulfoxidedppe 1,2-Bis(diphenylphosphino)ethaneE Entgegenee Enantiomeric excessEt Ethylet al. Et aliiG GlycineGly GlycineHATU O-(7-azabenzotriazol-1-yl)-N,N,N ,′ N -tetramethyluronium hexafluorophosphate′His HistidineHPLC High pressure liquid chromatographyi IsoL LigandLCMS Liquid chromatography-mass spectrometryLeu LeucineLG Leaving groupM Metalm MultipletMe Methyl

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Mol% Molar percentagen Numbern NormalNBS N-BromosuccinimideNMR Nuclear magnetic resonanceNuc Nucleophileo Orthop ParaPfp PentafluorophenylPG Protecting groupPh PhenylPhe PhenylalaninePPTS Pyridinium para-toluenesulfonatePr PropylPro Prolineq QuartetR ArginineR Rest groups SingletSer Serinet Tertt TripletTBAF Tetra-n-butylammonium fluorideTBS Tert-butyldimethyl silylTHF TetrahydrofuranTHP Tetrahydropyr-2-ylTIPS TriisopropylsilylTLC Thin layer chromatographyTrp TryptophanZ Zusammen

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Table of Contents

Abstract 2

Graphical abstract 3

List of Abbreviations 4

Table of Contents 6

Chapter 1, Introduction 7

Cyclic peptides 7

Peptide cyclization 10

Difficulties in cyclization 10

How to overcome these issues 12

Project objectives 16

Chapter 2 Development of a suitable Allylic Amination Methodology 20

Allylic amination 20

Results 21

Chapter 3 Synthesis of the Auxiliary 28

Results 28

Chapter 4 Coupling of the Auxiliary to an Amino Acid 33

Results 33

Chapter 5 Testing the Allylic Amination/Acyl-transfer Sequence 35

Results 35

Conclusion and Outlook 37

Acknowledgments 39

Experimental section 40

List of References 51

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Chapter 1, Introduction

Cyclic peptidesPeptides are important building blocks of nature. Peptides are build up from molecules called α-

amino 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, head-

to-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).

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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

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R’

R

NH2

CO2H

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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

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Figure 7 addition of cyanide catalyzed by c-[His-Phe]

Peptide cyclizationDue 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

LinearityThe 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.

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Site of ring closureAnother 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-terminusAnother 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.

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How to overcome these issuesThere 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 togetherInternal 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 L-

and 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

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Figure 11 peptide cyclization in which a carbosilane dendrimer ensures a pseudo-dilution atmosphere

Metal ion-assisted cyclizationsBy 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

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Sulfur-mediated cyclizationsAs 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 linkersNot 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

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Ring-contraction after lactone formationThe fifth methodology involves a reaction sequence consisting of oxo-ester formation and acyl-

transfer, 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 Boc-

group 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

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Recently another strategy employing an aza-michael addition and the earlier mentioned O-to-N acyl-

transfer 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 aza-

michael 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 objectivesThe 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).

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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 allyl-

containing 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

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When the correct reaction conditions are found, an acetate group will be placed at the ortho-

position 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).

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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.

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Chapter 2 Development of a suitable Allylic Amination MethodologyThe 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 aminationIn 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 fine-

tune both regio- as well as enantioselectivity.18

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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.

ResultsThe 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)-1,3-

diphenylallyl 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

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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 co-

workers. 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

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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

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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

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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 well-

known 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. Et 3N was chosen as

base, however, the results were comparable to the initial test results. The outcome of these

reactions is depicted in table 2.

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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.

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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

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Chapter 3 Synthesis of the AuxiliaryDuring 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

ResultsAt 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.

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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

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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

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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 “TIPS-

route” 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).

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Figure 36 synthesis of o-OAc methyl cinnamyl carbonate

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Chapter 4 Coupling of the Auxiliary to an Amino AcidBelow, 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.

ResultsFor 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

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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.

Figure 39 HPLC diagrams of racemic (left) and optically pure (right) coupling products (1 PDA Multi 1 / 254nm 4nm)

34

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Chapter 5 Testing the Allylic Amination/Acyl-transfer SequenceThe 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 o-

OAc cinnamyl acetate was unsuccessful (figure 40). Results are summed-up below.

Figure 40 the envisioned test allylic amination/O-to-N Acyl transfer reaction

ResultsWith the new allylic amination methodology and the auxiliaries in hand we could now test if the O-

to-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

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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 acyl-

transfer is much faster than the allylic amination reaction so another molecule of phenylalanine t-

butyl 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.

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Conclusion and OutlookThe 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.

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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

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AcknowledgmentsFive 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 end-

product 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!

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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

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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-5,6,11,12-

tetrahydrodibenzo[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

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General procedure for the allylic aminationIn a small capped vial, [Ir(dbcot)Cl]2 (4.50 mg, 0.005 mmol, 4 mol%) N,N-bis[(1S)-1-

phenylethyl]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.

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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), 2-

allylphenyl 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

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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 Et 2O.

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).

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General procedure for the deprotection of the alcohol after the acycloxylation reactionSynthesis 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 NH 4Cl 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

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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%). 1H 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).

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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 p-

toluenesulfonate (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

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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).

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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 NaHCO 3 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). 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). 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.

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In a flame-dried round-bottomed flask under N2, DCC (128 mg, 0.62 mmol, 1.2 equivalents)and Boc-

Phe-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).

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List of References

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1 C. J. White, A. K. Yudin, Nature Chemistry 2011, 3.2 T. Rezai, B. Yu, G. L. Millhauser, M. P. Jacobson, R. S. Lokey, J. Am. Chem. Soc. 2006, 128.3 P. Burton, R. Conradi, N. Ho, A. Hilgers, R. Borchardt, J. Pharm. Sci. 1996, 85, 1336-1340.4 F. Yokoyama, N. Suzuki, M. Haruki, N. Nishi, S. Oishi, N. Fujii, A. Utani, H. K. Kleinman, M. Nomizu, Biochemistry (N. Y. ) 2004,43.5 G. F. Gauze, M. G. Brazhnikova, Am. Rev. Soviet Med. 1944, 2, 134-138.6 M. Aumailley, M. Gurrath, G. Muller, J. Calvete, R. Timpl, H. Kessler, FEBS Lett. 1991, 291.7 H. Yoshida, K. Sugita, Jap. J. Cancer Res. 1992, 83.8 J. I. Oku, S. Inoue, Journal of the Chemical Society-Chemical Communications 1981, 5.9 Y. A. Ovchinnikov, V. T. Ivanov, Tetrahedron 1975, 31.10 U. Schmidt, J. Langner, Journal of Peptide Research 1997, 49.11 J. Chatterjee, D. F. Mierke, H. Kessler, Chemistry-a European Journal 2008, 14.12 H. Kessler, B. Haase, Int. J. Pept. Protein Res. 1992, 39.13 A. Amore, R. van Heerbeek, N. Zeep, J. van Esch, J. N. H. Reek, H. Hiemstra, J. H. van Maarseeen, J. Org. Chem. 2006, 71.14 M. Liu, Y. C. Tang, K. Q. Fan, X. Jiang, L. H. Lai, Y. H. Ye, Journal of Peptide Research 2005, 65.15 L. S. Zhang, J. P. Tam, J. Am. Chem. Soc. 1997, 119.16 J. Springer, T. P. Jansen, S. Ingemann, H. Hiemstra, J. H. Van Maarseveen, European Journal of Organic Chemistry 2008, 2.17 J. P. A. Rutters, Y. Verdonk, R. de Vries, S. Ingemann, H. Hiemstra, V. Levacher, J. H. van Maarseveen, Chemical Communications 2012, 48.18 B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103.19 M. E. Humphries, B. P. Clark, S. Regini, L. Acemoglu, J. M. J. Williams, Chirality 2003, 15.20 B. M. Trost, T. L. Calkins, C. Oertelt, J. Zambrano, Tetrahedron Lett. 1998, 39.21 R. Takeuchi, N. Ue, K. Tanabe, K. Yamashita, N. Shiga, J. Am. Chem. Soc. 2001, 123.22 P. Tosatti, J. Horn, A. J. Campbell, D. House, A. Nelson, S. P. Marsden, Advanced Synthesis & Catalysis 2010, 352.23 S. Chaffins, M. Brettreich, F. Wudl, Synthesis-Stuttgart 2002, 9.24 A. Singh, P. R. Sharp, Inorg. Chim. Acta 2008, 361.25 A. K. Chatterjee, T. L. Choi, D. P. Sanders, R. H. Grubbs, J. Am. Chem. Soc. 2003, 125.26 K. Kondo, M. Sodeoka, M. Shibasaki, Tetrahedron-Asymmetry 1995, 6.27 E. Thiery, C. Aouf, J. Belloy, D. Harakat, J. Le Bras, J. Muzart, J. Org. Chem. 2010, 75.28 S. Kobayashi, T. Semba, T. Takahashi, S. Yoshida, K. Dai, T. Otani, T. Saito, Tetrahedron 2009, 65.29 F. Ito, M. Iwasaki, T. Watanabe, T. Ishikawa, Y. Higuchi, Organic & Biomolecular Chemistry 2005, 3.30 M. Ohkoshi, J. Michinishi, S. Hara, H. Senboku, Tetrahedron 2010, 66.31 M. W. Williams, G. T. Young, J. Chem. Soc. 1964, 0, 3701-3708.32 A. Leitner, C. T. Shu, J. F. Hartwig, Org. Lett. 2005, 7.33 T. Nemoto, T. Sakamoto, T. Matsumoto, Y. Hamada, Tetrahedron Lett. 2006, 47.34 C. A. Kiener, C. T. Shu, C. Incarvito, J. F. Hartwig, J. Am. Chem. Soc. 2003, 125.35 M. J. Gresser, S. M. Wales, P. A. Keller, Tetrahedron 2010, 66.36 Y. Chan, C. Wu, S. Wu, T. Wu, J. Chin. Chem. Soc. (Taipei, Taiwan) 2002, 49, 263-268.37 F. Ito, M. Iwasaki, T. Watanabe, T. Ishikawa, Y. Higuchi, Organic & Biomolecular Chemistry 2005, 3.38 M. I. Dawson, P. D. Hobbs, R. L. Chan, W. R. Chao, V. A. Fung, J. Med. Chem. 1981, 24.